Medication Regulation in the US

Prescription Drugs, Controlled Prescription Drugs, Over the Counter Medicines, Homeopathy Drugs, Essential Oils,  Herbal Medicines, Supplements-  What Are the Differences and How Are They Regulated in the US?          by Algos staff

 

There is a dizzying array of medications, oils, herbals, and dietary supplements available to help with the control of pain.  Not all are equal, and not all that recommend using them have any training at all in pharmacology, toxicology, biochemistry, or medicine.  Much of what is available is completely untested for safety and efficacy.  This guide will help you decide what are the best choices for you and your body, what is hype, what is without evidence, and what may harm you.

 

Evidence based medicine is not only a concept developed around 1991, but is a living practice of using the highest available scientific and medical evidence to support a treatment for a given diagnosis.  But it was not always this way.  Early medicine derived from philosophy since anatomy and physiology of the human body were unknown.  The functions of the organs were a mystery and the concept of the nervous system was not even a fore thought in Greek and Roman times.  The function of the heart was not known until 1628.  The anatomy of the brain was not accurately described until 1664.  Medicine from 400 BC until the late 1800s adhered to a Hippocratic view of medicine as practiced with the Four Humors driving medical care:  phlegm, blood, black bile, and yellow bile.  Aristotle a few years later added hot, cold, wet and dry (the Four Basic Qualities) to the Four Humors.  All diseases and conditions were divided into categories in which there was too much or too little of each of the humors, therefore medicines (frequently herbs) were given to augment or reduce the production of these humors.   Bleeding patients was common.  The dark ages brought no real advancement in medicine due to preclusion by the Church to engage in dissection of the human body.  Mysticism, religion, folk tales and remedies all were intertwined with medicine through the renaissance with no scientific support whatsoever.

By the late 1700s the development of rather toxic medication was in vogue and this brought about the beginnings of homeopathy.  Homeopathy was developed by a itinerate bookseller Samuel Hahnemann in 1796, partially as a treatment that did not use toxic medications.  Homeopathy did not arrive in America until 1825.  Hahnemann noted similarities in the symptoms of certain diseases and the side effects of some medicines.  He reasoned that treating a disease exhibiting certain symptoms could be cured by giving the person a very dilute medicine known to cause the same symptoms, especially if the medicine were so dilute it could not harm the person.  Of course the dilution of the medicine reduced its potency from a strictly scientific standpoint, but Hahnemann contended the water itself used to make the dilution had sentient memory of what it was like before it was diluted, and with each dilution the medication became stronger.  Of course this was and is nonsense unsupported by any scientific experiment, and in fact the opposite has been proven.  Yet this did not dissuade Hahnemann from convincing others of this.   Hahnemann also touted that unlike the regular medical field, homeopathy would cure diseases so the homeopathic medicine could be stopped.  He claimed a wide array of complete cures for diseases that have no cure including cancer.  

Traditional medicine (regulars) continued manufacturing medicines ever more potent via distillation and separation in the early 1800s.  In 1806 medical licensure laws were first established to separate doctors from midwives (also practicing medicine at the time), Indian doctors or herbalists or botanicals (called “irregulars”), hydropaths (believed in the curative power of water), and the Thomsonians (self treatment in lieu of using doctors by employing herbs).  In the early 1800s, the botanical physicians were the greatest competition to the “regulars”, traditional medicine.  Botanicals were relatively safe but in “regular medicine”, the combination of an archaic medical system without understanding of physiology or anatomy yet using refined medications (including calomel or mercury chloride used in the 18th and 19th centuries, morphine isolated in 1806, strychnine in 1817, caffeine 1829, and nicotine 1828) proved disastrous to patients. The pharmacopeia of 1820 had only 100 drugs listed (first published pharmacopeia in the US) and most were herbal although some were toxic (arsenic, deadly nightshade, castor, ipecacuana, cinchona, hemlock, foxglove, quicksilver/mercury, antimony, essential oils, and others).   The treatment of cholera with purgatives employed by physicians in the early 1800s (frequently trained by apprenticeship with other physicians rather than through any formal medical training) cost many people their lives.  The adage “cholera has a 1/3 death rate but when treated by a physician, the death rate rises to 50%” was not untrue.  Gradually, the legislatures of states lost confidence in the very poor regular medical system that seemed to kill more patients than they cured through the use of mercury treatments, bloodletting, burning of cancer with nitric acid, and the use of other toxic drugs.  Regular medicine was in full competition with other treatment systems that were less deadly including homeopathy, Thomasonians, botanicals, irregulars, midwives, and folk doctors”. Subsequent de-licensure of the regular medical profession occurred in most states from the 1820s until the 1870s.  The eclectic medical system was an extension of Thomsonian medicine and included native American medicine.  The first hospital for eclectic medicine was founded in New York in 1827 (United States Infirmary) and the first eclectic medicine college, the Reformed Medical College in 1829.  Several other eclectic medical schools opened over the next 70 years.  By 1840, the botanicals and Thomasonians and eclectics combined their forces and philosophies, forming what was known as eclectic medicine and eclectic schools (this was a throwback to eclectic medicine practiced in ancient Greece and Rome).  By 1845, homeopathy became the most potent competitor to regular medicine, with homeopathic schools, hospitals, and practitioners spreading throughout the US.  Regular doctors in the US continued to treat the population with very toxic substances, especially mercury chloride (calomel) that made many people perpetually ill.  

It was not until the American Medical Association began to bring some legitimacy to the profession to the regular medical profession before the Civil war, and the obvious need for physician surgeons during the war that propelled the medical profession back into the good graces of the legislatures of the states.  New anatomy texts from Europe were being published at that time, advancing the understanding of the anatomy and physiology of the normal and the abnormal.  The development of the use of electricity using static electricity generators coupled to a Leyden jar advanced the portability of medicine. The late 1880s saw the implementation of electric lights and electricity wired into people’s homes.  Electrotherapy began to be practiced as a healing art and electrotherapy schools were opened to assist in training.  Homeopathy remained a potent competitor to regular medicine reaching its height around 1890 when there were 14 homeopathic schools, 8 eclectic schools, and 93 regular schools, but by 1900 there were 22 homeopathic schools, 10 eclectic schools, and 121 regular schools.  Other competing systems of treatment began to emerge in the late 19th century with the invention of osteopathic medicine in 1892 by Andrew Taylor Still, a frontier physician without any formal medical education, and chiropractic manipulation to cure all kinds of diseases invented by Daniel David Palmer of Iowa in 1895.  Medical education became more standardized after publication of the Flexner report in 1910 caused the closure of the majority of the 155 medical schools in the US due to their poor quality.   Most of these schools were effectively trade schools, owned by one or a few doctors, with little opportunity for practicing medicine or participating in medical care for most students.  There were no laboratory requirements or dissection in many of the schools and most instructors were part time local doctors.  The outcome of Flexner and the standardized medical education recommendations was profound with only 85 schools still open in 1920 and 66 medical schools by 1935.  All homeopathy schools and electrotherapy schools had closed by 1920.  The last eclectic school closed in 1939 (Cincinnati).

             Up until the 1950s, most medical practice was conducted on the basis of apprenticeship learning or observations about single patient responses to procedures and medicines without a placebo control or randomization.   Without randomization or controls, data obtained from studies is flawed, with possible bias effects, however the understanding of problems with biased studies did not take hold in traditional medicine until the 1970s and became codified in the 1990s under the development of evidence based medicine.  Very specific criteria were developed to determine the value of a given study and how to view the cumulative sum of all the available scientific literature to draw rational and widely applicable solutions.  These criteria include the following: 

• Trial participants are randomized to receive one treatment arm or another without the patient nor the physician having a choice.  This significantly reduces physician bias and patient responses based on expectations.

• Both physician and patient are blinded to which limb of the trial they are enrolled in.  This also eliminates physician bias and telegraphed expected responses.

• A placebo controlled trial is used whenever possible.

• A drop out rate of the participants of no more than 20% is acceptable to make the study valid.

• There are safeguards to prevent financial inducement of a particular result

• The observer is usually a different person than the experimenter.

• There are minimal study protocol deviations.

• The study must be sufficiently powered with enough participants to provide positive statistical and clinical meaningful outcome measurements.  A NNT evaluation is preferred (number needed to treat to obtain one patient with a 50% response rate).   A risk evaluation is also needed as part of the statistical analysis.

 

The most complete and validated measure in evidence based medicine is the systematic comprehensive evaluation of studies, also called a systematic review.  The Cochrane collective is a standardized method of creating such a systemic review of all the applicable and acceptable randomized controlled trials (RCTs) and permits medical evidence to be graded into four categories from very weak to strong evidence either for or against a procedure or outcome.   Therefore Cochrane represents the most applicable evaluation of overall outcomes from studies.  This protocol supplants single randomized control trials or case series with respect to evidence based medicine.  Conclusions from a Cochrane review supplant the conclusions drawn from individual studies.

 

Other evidence for a procedure or intervention includes health insurance coverage evaluations of the literature, FDA approval, FDA regulations, medical society evaluation of a procedure or intervention, and isolated studies in the following order of importance:  double blind placebo controlled randomized large multicenter trials with low dropout and significant clinical and statistical results; same but single center trial; cross over studies with the participants blind; single blind randomized controlled trials;  case series with historical or unpaired control group; longitudinal case series (followed in time); small group reports; pilot study clinical trials; case observations, single case observations/opinion, animal trials, bacterial response trials, chemical reaction observations, theory of possible reactions/benefits. 

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As you can see in the above chart, there is no FDA monitoring of essential oils or homeopathic medications, even though by law the FDA is supposed to monitor and regulate homeopathic medicines.  Up to this point they concede they do not know how to do so, since by definition the concentrations of ingredients in homeopathic preparations are serially diluted to the point there are no substances remaining in the water, therefore the FDA has simply not monitored this industry.  However, the contents of homeopathic solutions are not verified by any agency of the government nor tested consistently by any third party organization, and some homeopathic remedies may contain overt prescription drugs being added illegally in order that the homeopathic remedy would actually have some perceivable effect by the patients.

 

Who Prescribes These Medicines?   

There are enormous differences in who actually prescribes or recommends these medications/remedies.  Here are some estimates.

 

 

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CONTROLLED PRESCRIPTION MEDICATIONS

These include opioids, anxiety medications (benzodiazepines), stimulants including amphetamines, etc.  Both the Drug Enforcement Act of 1971 via the Drug Enforcement Administration and the Food and Drug Administration via the Pure Food and Drug Act of 1906, with the subsequent law of 1938, and amendments of 1951 and 1962.  These medications are the most regulated of all drugs, requiring prescription for the vaguely defined “legitimate medical purpose” in the “usual course of medical practice”.  The DEA developed a scheduling system for drugs with those in Schedule I having no useful medical purpose.  This Schedule includes LSD, marijuana, ecstasy, PCP, and many opioid narcotics that are not legal in the US including heroin.  Schedule II includes most of the currently used opioids including morphine, oxycodone, oxymorphone, methadone, tapentadol, meperidine, levorphanol, hydromorphone, and as of Oct 2014, hydrocodone.  Hydrocodone had been misclassified by the DEA for more than 4 decades as a Schedule III drug (one with less abuse potential than a Schedule II drug) and because of the easy access to the drug (could call it in to a pharmacy, have refills lasting up to 6 months, etc), it became the most abused drug in the US, and was a gateway drug to more high potency drugs.  It took over 14 years of petitioning the federal government before the DEA and FDA would change the drug into a Schedule II drug, and only after millions became addicted to opioid painkillers due to physician overprescribing of hydrocodone for every bump and bruise.   Physicians, nurse practitioners, physician’s assistants, dentists (DMD, DDS), podiatrists, veterinarians, and some clinical nurse specialists/midwives can prescribe these potent drugs with a special DEA license and in some states an additional state narcotic prescribing license is necessary.  Methadone for addiction requires a special DEA license and buprenorphine (e.g. Suboxone) being prescribed for addiction requires a special DEA waiver and training.   Opioid deaths from prescription opioids continue to rise in spite of tightening of federal, state, local laws and regulations, with 18,400 people killed by these drugs in 2014.  For every death there are 108 people that become addicted to prescription opioids.  The tightening regulations have reduced the availability of the opioids yet, more people are dying each year from the prescription opioids.  Of concern is the tremendous increase in heroin deaths that have tripled in four years, and are now half the number of prescription opioid deaths and rising.  Heroin is a cheap substitute for prescription opioids, readily found on the street, but due to it being laced with fentanyl (a drug much more potent than heroin) and inconsistent purity, more people are overdosing and dying from this drug.   Fully 80% of those using heroin first became hooked on prescription opioids being prescribed by a doctor in excess quantity or for excessive lengths of time for conditions that either shouldn’t require opioids or the condition should have long ago healed.   The patient experiences withdrawal symptoms when trying to stop the drug, and therefore continues to use prescription opioids and or heroin to stop the withdrawal symptoms rather than trying to “get high” in the majority of cases.  US doctors prescribe 4 ½ times as much opioid narcotics per capita compared to Europe and 8000% as much (per capita) as the rest of the world.  Clearly out of control prescribing by physicians started and is maintaining the opioid epidemic of death and addiction being experienced in the US, and the associated crimes (pharmacy robberies, theft of property to sell for drugs, prostitution, etc.)  Schedule IV drugs have less abuse potential than Schedule III, but still require a prescription.  Schedule V drugs may be obtained with a prescription or without a prescription as a behind the counter pharmacy dispensed drug.  Although the FDA regulates these drugs and both safety and efficacy must be proven, the FDA falls short in requiring only 12 week studies of opioids, and does not require evaluation of chronic prescribing or real life dosage escalations that occur.  There is a clarion call for the FDA to change this given the large number of deaths per year and the millions in the US becoming chemically dependent on the drugs with no long term high quality studies to support their usage.

EBM:  No Studies to Support Long Term Safety or Efficacy.  Many retrospective studies show dose related increases in death rates and addiction.   EBM supports only short term limited dosage usage of these drugs.

 

PRESCRIPTION MEDICATIONS

Prescription medications used for pain that are not controlled substances require a physician’s (or provider) prescription prior to dispensing such medications.  Such prescriptions may be called in (by the physician, provider, or their designee), written, faxed, or e-scripted to the pharmacies and may contain refills, frequently up to a year.  Prescriptions used for pain are the anticonvulsants, antidepressants, anxiolytics, topicals, muscle relaxants, alpha antagonists, and other classes of drugs discussed elsewhere in this website.  These medicines require a new drug application (NDA) or if already on the market and seeking a new use, require an abbreviated new drug application (ANDA) from the FDA.  The FDA requires studies of high quality that demonstrate safety and efficacy, and that the manufacturing of such drugs is performed within the parameters defined by Good Manufacturing Practices (GMP).   The process of getting a new drug approved by the FDA requires many years and tens of millions of dollars.   The drugs are scrutinized at several levels by the FDA before approval is granted, and a post marketing surveillance of the drug is continued after release onto the market.  The FDA has the ability to require modifications to manufacturing or labeling of the drug, restrict usage of the drug, recall the drug, or stop the production and release to the public at any time.  These measures are provided to optimize the assurances of safety to the public with full disclosure of potential side effects.  The FDA did not always have such stringent requirements, that have progressively become stricter over time.

The original Federal Food and Drugs Act of June 30, 1906, first brought drug regulation under federal law. That Act prohibited the sale of adulterated or misbranded drugs, but did not require that drugs be approved by FDA. In 1938, Congress passed the Federal Food, Drug, and Cosmetic Act (the FD&C Act), which required that new drugs be approved for safety. The active ingredients of many drugs currently on the market were first introduced, at least in some form, before 1938. Between 1938 and 1962, if a drug obtained approval, FDA considered drugs that were identical, related, or similar (IRS) to the approved drug to be covered by that approval, and allowed those IRS drugs to be marketed without independent approval. Many manufacturers also introduced drugs onto the market between 1938 and 1962 based on their own conclusion that the products were generally recognized as safe (GRAS) or based on an opinion from FDA that the products were not new drugs. In 1962, Congress amended the Act to require that a new drug also be proven effective, as well as safe, to obtain FDA approval. This amendment also required FDA to conduct a retrospective evaluation of the effectiveness of the drug products that FDA had approved as safe between 1938 and 1962 through the new drug approval process. The FDA then conducted a study on the effectiveness of over 3,400 products from 1962 to the early 1970s called the Drug Efficacy Study Implementation (DESI).  Some drugs studied under DESI were found to be ineffective and were removed from the market by the FDA.  However in 1983, an injectable vitamin E drug that was “grandfathered” under the prior regulations resulted in the deaths of 40 infants, and was pulled from the market by the FDA.  This caused the FDA to re-examine the “grandfathering” of drugs that were not FDA approved and engage in what became known as “Prescription Drug Wrap-up”, i.e. addressing all marketed unapproved drugs, not limited to DESI.  This did not eliminate all grandfathered drugs from having to prove safety and efficacy due to the continued existence of the legislative amendments of 1938 and 1962, but narrowed the number of drugs significantly to only a few that retained grandfathering privilege.  Since 2011, the FDA has taken a very aggressive posture against some drugs that were grandfathered in but were marketed without FDA pre-approval (as allowed by law).  A manufacturer may submit a NDA for a grandfathered drug and obtain FDA approval, hike the price of the grandfathered drug by 10-100 times, and then the FDA will stop the other manufacturers from making the grandfathered drug.  The FDA says this is to assure safety, but in fact this is costing the public millions of dollars in excessive costs of what was a generic drug that now becomes a brand name drug under the FDA.

EBM has good support in premarketing and post marketing studies for both safety and efficacy for these drugs.

 

BEHIND THE COUNTER MEDICATIONS

 These medicines are available to the public on authorization by the pharmacist without a prescription for the medication.  These drugs include Schedule V drugs such as a large number of low codeine content drugs,  dihydrocodeine, diphenoxylate, ezogabine, lacosamide, and in some states, pseudoephedrine (used to make methamphetamine).  Usually the pharmacist will have the patient sign a log book for the cough medicine or diarrhea treatment drug or Vimpat (anticonvulsant drug) then will dispense the medication after a few questions.  These drugs are now listed in most PMP (patient monitoring program) databases so frequently obtaining these drugs from multiple pharmacies will send up a red flag to the pharmacist that checks these databases, and the pharmacist may refuse to dispense anymore of the drug.

EBM- limited support for some of these drugs, more for those introduced more recently.

 

HOMEOPATHIC MEDICATIONS

Largely a belief system similar to a religion, homeopathy had its roots not in science but in a rather unfortunate misinterpretation of the side effects of medications being linked to the symptoms of diseases in the mind of Samuel Hahnemann in 1796, and the erroneous conclusion that profoundly dilute solutions of such medications would be effective treatments for diseases.  The dilutions specified by Hahnemann were absurdly dilute, such as 100 to the 30th power of dilution.  He also believed most diseases originate from “miasms” that are primarily venereal diseases.   This rather bizarre system of medicine came to the US in 1825 and homeopathy schools were set up in several major cities.  Hahnemann believed there was only one remedy necessary for a collection of symptoms rather than 3-6 as are employed today.  He said “In no case under treatment is it necessary and therefore not permissible to administer to a patient more than one single, simple medicinal substance at one time…. As the true physician finds in simple medicines, administered singly and uncombined, all that he can be possibly desire … he will, mindful of the wise maxim that “ it is wrong to attempt to employ a complex means when simple means suffice”, never think of giving as a remedy any but a single, simple substance”

This type of completely safe but completely ineffective treatment became wildly popular as a substitute for the toxic medications used by physicians.  Homeopathy claims not to merely treat, but to cure diseases. By 1845, homeopathy was the greatest competition to traditional medicine (regulars).  By the late 1880s, there were homeopathic hospitals in nearly every city in the US with more than 50,000 people.  The popularity of homeopathy continued until the early 20th century when the last homeopathic hospital and homeopathic school finally closed in 1920, supplanted by traditional medicine and the power of the American Medical Association.

In 1938 at the behest of a US Senator from New York, Royal Copeland, who was a practicing homeopath, convinced Congress and the FDA to grandfather in homeopathic medicines that were listed in the HPUS, the Homeopathic Pharmacopeia of the United States (now available only on-line to subscribers).  The 1938 Food Drug and Cosmetic act (regulates prescription pharmaceuticals), had many loopholes placed into the law that made regulation of homeopathic medicines impossible.  These exemptions for homeopathic “remedies” (a code word used by homeopaths meaning drug) by the FDA include:

• Not required to submit new drug applications to the FDA

• Exempt from good manufacturing practice requirements related to expiration dating

• Exempt from “finished product testing for identity and strength”

• May contain much higher amounts of alcohol than other drugs (that are limited to 10%)

In 1988 Congress decided to allow sales of the homeopathic remedies over the counter at pharmacies and grocery stores instead of requiring preparation by homeopaths or by a pharmacist.  The 1994 law Dietary Supplement Health and Education Act (carved out exemptions for the supplement industry) did not include or regulate homeopathic “remedies”.   Finally in 2015, the FDA held hearings on homeopathy due to it being a multibillion dollar business that remains almost completely unregulated in the US.  They asked several probing questions about homeopathy including why homeopathic medicines, most of which are OTC in pharmacies and other stores, are not regulated like OTC medicines.  They also asked if consumers and health care providers were being given adequate information about the products in order to make informed decisions about their use given the extremely sparse labeling and information available about each product.  Finally, the FDA asked for data regarding safety and efficacy of homeopathic medicine.  The outcome of these hearings is undetermined as of Feb 2016.

            Homeopathic medicines are available over the counter as commercially produced products.  Most violate the principles of homeopathy in that only a single remedy was to be used for a particular collection of symptoms, but since there is no one to “diagnose” and tell patients which nostrum to use, the manufacturers have bastardized the industry to dump sometimes 10-20 substances into one bottle.  Of course these are profoundly dilute substances, containing no more than one molecule in an entire ocean of volume, so they are for all purposes, pure water, or at least as the purity of the water used to make the dilutions.

            Because homeopathic practitioners are not scientists and most are not doctors, and because most homeopathic medicines are sold OTC without any prescription or formulation specific to the disease treated, the quality and quantity of scientific studies is extremely poor.   Most homeopathic studies are of the type “I gave this to a patient and they got better, therefore it proves the effectiveness of homeopathy”.  Of course without a placebo control, the patient may be responding to the placebo effect, to the counseling that goes with homeopathy, or because they were getting better anyway with or without intervention.  The homeopaths themselves may introduce bias into their published studies since they may offer additional services such as counseling and other therapies to those receiving their homeopathic drugs but not to a control group (if any), and that the homeopaths themselves are making the observations and collecting the data from patients, thereby introducing significant bias.  Additional concerns are that homeopathic medicines have not been analyzed and it has been shown some are adulterated with prescription drugs (unknown to the patient) in order to make them effective.  Because of the lack of FDA regulation of the industry, there are no studies of safety or efficacy required before marketing, claims may be made of healing or cures without substantiation, and the actual content of what is in these drugs is wholly unknown due to the lack of FDA or standardized testing of the drugs.   Cochrane studies of these drugs suffer from the lack of clinical studies being conducted using evidence based medicine randomized controlled trials or have serious bias issues based on the lack of independent observation and evaluation of outcomes.  The journal Schmertz in 2012 evaluated complementary and alternative medicine techniques for treatment of fibromyalgia and stated “homeopathy is not recommended”.   For otitis media, a systematic review was performed of different therapies and homeopathy was found to have insufficient evidence to support its use (Medicine Baltimore 2016 Feb;95(6):e2695).  More telling is that in the homeopathy publications there is limited evidence.  A review of controlled clinical studies of homeopathy published in Homeopathy Oct 2015 (p328-32) found “The question whether homeopathic intervention differs from placebo awaits decisive answer”.  The article discusses that of the 36 systematic reviews of homeopathy, the majority show no effect or were inconclusive.  Animal studies also demonstrate lack of proof of effectiveness of homeopathy (BMC Vet Res Sep 15;11:236).   The journal Evidence Based Complementary and Alternative Medicine published a systematic review of CAM therapies for the treatment of fibromyalgia (2015:610615) and found there was inconclusive evidence to support homeopathy.   Other systematic reviews have found very small effects of homeopathy compared to placebo but with caution in interpreting these findings due to very poor quality data (Syst. Rev 2014 Dec 6;3:142).  One systematic review found that over 90% of homeopathic studies conducted are of very poor quality and had to be discarded in an evidence based medicine analysis (Forsch Komplementmed 2013;20(5):376-81).

EBM does not support the use of homeopathy due to extremely poorly conducted studies by the vast majority of homeopathic practitioners that fail to understand or adhere to scientific principles in the design and conduct of their studies.  The remaining studies show very limited and inconsistent results.  Given that this is a 3 billion dollar industry in the US and has virtually no regulation and no scientific support, homeopathy should be employed only for what it is: an unscientific non-medical belief system that is based on flawed logic, bizarre concepts, and without any significant proof of either safety or efficacy.

 

OVER THE COUNTER MEDICATIONS

Over the counter drugs (OTC) are those that do not require a prescription from a physician or provider, and may be sold in pharmacies, via mail, or in any other store.  These include oral, some rectal, some otic, and topical medications.  The 1962 law establishing DESI also included OTC drugs, but the FDA concluded they lacked the resources to assure all OTC drugs were safe and effective.   Therefore in 1972, the FDA began a process of reviewing OTC drugs through rulemaking by therapeutic classes (e.g., antacids, antiperspirants, cold remedies, etc.)  Final monographs were created for each class of drugs that set forth the allowable claims, labeling, and active ingredients for OTC drugs in each class.  Drugs marketed in accordance with these final monographs are considered by the FDA to be generally recognized to be safe and effective, and do not require FDA approval of a marketing application.  However there are a number of so called negative monographs that list therapeutic categories (e.g. OTC daytime sedatives) in which no OTC drugs can be marketed without approval.  Finally, the FDA published a list of active ingredients that cannot be used in OTC drugs without approved applications because there are inadequate data to establish they are generally safe and effective (e.g. phenolphthalein in laxative products).   The manufacturing process of these drugs is only loosely regulated by the FDA and only rarely does the FDA actually check the contents of the drugs being manufactured.  Because the bottles for these drugs are sitting on the shelf available to consumers, tampering with the drugs is a potential issue, however following the cyanide tampering of Tylenol resulting in deaths in 1982, the FDA adopted anti-tampering seals that are located on the top of each bottle, and the body of the bottles are constructed of relatively thick plastic.

            In summary, OTC drugs are only quasi-regulated by class, with the active drug and excipients not requiring pre-approval by the FDA as long as there is a FDA published class monograph.   The amount of the permissible drug per dosage is specified in these monographs, that have been changed most recently to reduce the amount of acetaminophen permitted per dosage unit.

EBM for OTC medications for pain supports the use of naproxen sodium containing drugs (e.g. Aleve), ibuprofen (Advil, Motrin IB), and aspirin in systematic reviews.  Acetaminophen is less effective than NSAIDS for osteoarthritis pain in systematic reviews.  

 

COMPOUNDED MEDICATIONS

            Medications that are compounded for pain purposes may be oral, suppositories, sublingual, topical, or injectable.  It is because of issues with the latter that has resulted in a sea change in the industry because of poor techniques resulting in death and illness.  Compounding has been used for centuries by pharmacists and in fact, up until around 1950 when mass manufacturing of pills became commercialized, most drugs were compounded.  But compounding continues even until today because there are some advantages to patients with specific combinations or preparations of drugs that are not commercially available.  Compounding pharmacies represent a specialized type of pharmacy with the capability of mixing drugs together in combination and placing them into a pill, capsule, liquid, or topical form for patient use.  Traditionally, compounding pharmacies would receive a prescription for a specific patient for the drugs to be compounded, then make enough for one patient.  The more commonly compounded preparations, would result in the pharmacy creating enough compounded drug for up to 10 people, then wait for the prescriptions to come in, then simply distribute the compounded drug that had been held in stock.  It is economically more feasible to compound for more than one patient, but this draws the scrutiny of the FDA that regulates manufacturing of drugs (commercial preparation for more than one patient).   Compounding pharmacies had been able to get away with this for some time because a Florida court order and a 2002 US Supreme Court decision prevented the FDA from regulating compounding pharmacies, as they are regulated by the state board of pharmacy in each state.  Each state board had their own criteria for a compounding pharmacy, with some state boards inspecting the compounding pharmacies.  

The rise of topical compounding with compounding pharmacies shipping nationwide was covered by the reciprocal agreement between state pharmacy boards or state laws that permitted an out of state compounding pharmacy to sell to people in another state as long as the pharmacy was regulated by the state board of pharmacy in the state in which they produced the product.  This encouraged compounding pharmacies to increasingly act as manufacturers.  The problems associated with such arrangements finally became known to the entire US when in 2012, the New England Compounding Center (NECC) began shipping injectable steroid drugs that were tainted with black mold exserohilum rostratum.  This caused a number of patient deaths and many people needing expensive IV treatments with antifungal agents for 3-6 months.  Congress investigated and found the NECC was advertising to pain doctors that they would produce a cheaper alternative to Depomedrol and would remove the preservative (MGPC) because of some doctor and patient concerns that the MGPC could cause neurological problems (there was never any demonstration of such- it was theoretical).  The doctors then fabricated a prescription for a non-existent patient or wrote a prescription for a case of vials of the drug (clearly not intended to be used on one patient) and the NECC manufactured a case of the drug for the doctor.  However, the facilities used in the manufacturing were dirty, located inside a recycling plant, and had the air intake ducts from the outside next to garbage that was growing the black mold.  This caused interior contamination and therefore manufacturing mass quantities of tainted steroids.  In retrospect the NECC had been sanctioned by the Massachusetts state board of pharmacy and knew that it was a problem pharmacy but did nothing about it.  It turns out, one of the sister companies owned by the same people had an employee pharmacist who also served on the Massachusetts board of pharmacy.  The FDA was called before Congress to explain why they were not regulating this pharmacy and told Congress there were not permitted to do so by law, so Congress changed the law in 2013 with passage of the Drug Quality and Security Act.  Specifically, this requires all compounded drugs to be made under sanitary conditions.  This act also describes conditions under which certain compounded human drug products are entitled to exemptions from three sections of the Food Drug and Cosmetic Act (FDCA) requiring compliance with good manufacturing practices, labeling with adequate directions for use, and FDA approval prior to marketing.  A new class of “outsourcing facilities” was created with exemptions from the FDA approval requirements and labeling requirements but not an exemption from the good manufacturing practices.    The standards for compounding pharmacies include good manufacturing practices and sterility.

EBM has very limited numbers of studies for compounded drugs, therefore it is difficult to support or refute the effect of some compounded drugs.

 

SUPPLEMENTS

This class of drugs (and they are indeed drugs) was expanded in scope by the 1994 law Dietary Supplement Health and Education Act (DSHEA).  Prior to that time, supplements consisted of vitamins naturally occurring, minerals, and some herbs.  However a US Senator Orin Hatch with deep ties to the supplement industry sponsored DSHEA and has defended DSHEA against any resolution or act that would limit or restrict DSHEA.  The DSHEA vastly expanded the definition of what was considered a supplement.  The new definition includes vitamins, minerals, herbs or other botanicals, a concentrate, metabolite, constituent, extract, or combination of the above.  These definitions now permit manufacturers to synthetically create any metabolite that would be produced in the body from a herb or supplement (tens of thousands of chemicals) and market them as supplements.  The supplements must be labeled as a dietary supplement or the name of the supplement followed by the word supplement, quantity of pills or capsules, “nutritional information” including serving size (like food labeling)/amount/% daily value if established, the net weight of any proprietary blend plus the contents in descending weight order of the blend, part of the plant used if an herb or botanical, name and place of business or distributor, complete list of ingredients, safety information, a disclaimer that the product is not intended to diagnose/treat/cure/prevent disease, and any claims of benefit ascribed to the supplement such as “supports heart health”.  The drug cannot claim to treat or cure any disease so the manufacturers have skirted this part of the law by using “supports” as a code word to consumers for treatment and cure.

Under DSHEA the supplement manufacturers do not need to receive FDA approval before marketing dietary supplements that were marketed in the US before 1994.  Ingredients not grandfathered in since 1994 must be reviewed for safety or reasonable expectations of safety by the FDA.  However the review is cursory, uses content analysis data provided by the manufacturer and has been shown these contents analysis are sometimes fabricated out of thin air, not reflecting the true content of supplements that in some studies have found 1/3 of supplements contain prescription drugs that are being added illegally by manufacturers.  This is because many supplements simply don’t work, so the manufacturers defraud the public by adding prescription drugs to the supplement without telling consumers.  This is particularly true of products treating arthritis, erectile dysfunction, and weight loss.

            The DSHEA was effectively a deal between the supplement manufacturers and the FDA in which the industry was given carte blanche to manufacture and sell untested drugs with no demonstration of safety or efficacy, in exchange for the supplement industry conducting the studies that would support safety and efficacy.  The supplement industry however elected to not conduct any safety or efficacy studies since they were given unfettered free reign to make these drugs without any requirement of safety or efficacy.

            The FDA is prohibited from keeping any supplement from entering the marketplace, does not require any safety or efficacy studies, and can only act to remove a product after it has caused injury in a number of people or has found to fraudulently contain illegally added prescription drugs.  The FDA does have the power to inspect the manufacturing plants in the US, but rarely does so, and finds serious problems in more than half the inspections, but does not inspect the plants overseas where the vast majority of the supplement raw material is actually manufactured.  

            The FDA does not have an adverse event reporting system for supplements as is in place for drugs or other devices approved by the FDA, therefore supplement injuries are vastly underreported.  Only the most serious adverse events are reported, missing most adverse events that might have clued the FDA years in advance of more serious health problems developing due to the supplements.  More than 23,000 emergency department visits per year are due to supplement side effects, and hundreds of thousands more visit their doctors offices for side effects. But almost none of these are reported, since the hospitals and doctors frequently do not link supplements to specifically illness, and patients not infrequently withhold this critically important information about their taking supplements from their physician. Indeed, injuries due to supplements (e.g. gastrointestinal life threatening bleeds) may not even be connected to the use of the supplement in the mind of the consumer or medical professions since the supplements are assumed to be safe and the patient may not link the long term development of symptoms to a supplement..  However some arthritis supplements contain up to 5 different prescription NSAIDS that may cause serious GI bleeds, kidney failure, strokes, heart attacks, etc., but the supplements are never connected to these since any analysis information submitted by the manufacturer to the FDA may be fabricated.  The FDA does not have the resources to test the nearly 100,000 products, each of which can change their contents overnight without notification.  If a supplement is withdrawn from the market by the FDA, the manufacturers simply place a new label over the drug and begin selling it the next day.  Recalled supplements are not actually recalled but the warehouse stock is sold out as fast as the manufacturer can sell it.  The entire industry is full of graft and corruption, posing a serious threat to the health of the US population, but Congress, blocked by Orin Hatch, will not change the law, therefore the FDA is powerless to regulate this out of control drug industry.  There is no longer anything “natural” about supplements that are chemicals and drugs manufactured as drugs from synthetic materials and skirt around other FDA drug laws.  David Kessler, the commissioner of the FDA when DSHEA was approved stated “Congress has shown little interest in protecting consumers from the hazards of dietary supplements, let alone from the fraudulent claims that are made, since its members apparently believe that few of these products place people in real danger.  Nor does the public understand how potentially dangerous these products can be.”

EBM has low level support for devil’s claw, ginger, turmeric, and bromelain for the treatment of pain.

  

ESSENTIAL OILS

Essential oils are obtained from plants and spices via distillation or extraction techniques.  These are frequently used as an alternative medicine method of treating disease or bodily dysfunction.  The FDA theoretically regulates essential oils on the basis of the claims made about the product’s use and whether the claims are that it treats or heals anything.  Cosmetics, such as a shower gel intended to cleanse the body or a perfume/cologne do not require pre-approval by the FDA, and are removed from the market only after they have been shown to be unsafe.  Essential oils used for medical purposes however are not cosmetics, and require FDA approval for safety and efficacy prior to marketing, yet the FDA fails to regulate these drugs as required by law.  The FDA regulates labeling for drugs while advertising claims are regulated by the Federal Trade Commission.  The FDA states it determines a product’s intended use based on factors such as claims made in the labeling, on websites, and in advertising, as well as what consumers expect it to do. The FDA also states they look at how a product is marketed, not just a word or phrase taken out of context. Finally, in theory, the FDA makes decisions on a case-by-case basis.  However with essential oils (aromatherapy), the FDA rarely makes any decisions at all, allowing an entire industry to skirt the federal drug laws in this country.

 

The FDA website defines a drug as a substance that is “intended for a therapeutic use, such as treating or preventing disease, or to affect the structure or function of the body, it’s a drug. For example, claims that a product will relieve colic, ease pain, relax muscles, treat depression or anxiety, or help you sleep are drug claims. “  The website www.bulkapothecary.com makes the following claims about aniseed oil as of 3/12/16: “Botanical Name: Pimpinella anisum Plant Part: Seeds Extraction Method: Steam Distilled Origin: India Common Uses: Aniseed is considered to have antiseptic, anti-spasmodic, carminative, diuretic, expectorant, galactagogue, stimulant and stomachic properties.”  According to the FDA, these claims are medical claims and would therefore subject this product to regulation as a drug.  Many essential oil manufacturers make such claims of medical therapy benefits from their products. 

There are three routes essential oils may be used:  topically, inhaled, or internally.  Topical essential oils have been used for thousands of years.  Pressed oils (dilute, impure) were used by Dioscorides, described (along with beliefs of the time regarding their healing properties), in his De Materia Medica, written in the first century.  More concentrated forms became available after Avicenna began distilling the oils in the 11th century AD. Now, extraordinarily concentrated oils are available- so concentrated that they may cause skin reactions when administered undiluted to the skin.   Those who mix topical oils are called “aromatherapists” and use several oils mixed together in an attempt to harness properties of these oils for healing.  However there is virtually no clinical or scientific evidence of effectiveness of any of the individual oils, much less any combination of oils.  The mixing of these oils as a concoction is based in tradition without scientific study or proof.  Therefore, essential oil compounding is effectively a belief system rather than a medical treatment, despite the aromatherapists claims of wildly exaggerated medical cures and treatments. 

The following are dermal irritants and may cause redness or blotchy skin irritation that may be painful:

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There are also dermal sensitizers that are not recommended for aromatherapy use due to allergic reactions.

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Finally, there are photosensitizing oils that may cause pigmentation changes in the skin when exposed to light:

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If some aromatherapy oils come in contact with the eyes, they may cause severe eye injury.

There is only very low levels of evidence that any essential oil helps with symptoms of pain, with one Cochrane review concluding: “Aromatic lavender essential oil applied by acupressure may reduce subjective pain intensity and improve lateral spine flexion and walking time compared to untreated participants (one trial, 61 participants,very low quality evidence).”

Oral essential oils are advocated by a very few people, given the extreme potential for toxicity. 

Quality of essential oils:  most essential oils are of unknown content since they are not typically tested for purity or whether the content is as advertised on the label.  The FDA would require testing if they were to regulate essential oils as required by the Food and Drug Act, but since the FDA for the most part ignores this requirement, the essential oil industry has no required oversight or truth in advertising. One recent action against a manufacturer of essential oils that claimed to protect against Ebola viruses, treating Parkinson’s disease, Alzheimer’s disease, autism, multiple sclerosis, and breast cancer, however the FDA action was simply a letter asking for clarification of whether the essential oils were being used topically or as a supplement.

SUMMARY: Essential oils are being marketed to treat a variety of health conditions in direct violation of the Food and Drug Act, may have skin reactions or toxicities associated with their use, and are totally untested as to purity or content.  There is extremely limited evidence there is any essential oil that helps with pain issues.

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