7
Steroids
Freddy Homburger, an oncologist as well as an enthusiastic watercolorist, admired the work of the acclaimed French painter Raoul Dufy long before he actually met the artist. It was, in fact, that admiration that brought the two men together. In 1949, Dr. Homburger saw a photograph in Life magazine of Dufy, then seventy-two years old, that showed the crippling effect of rheumatoid arthritis (RA) on the artist. Familiar with recent trials of adrenal hormone (cortisone acetate) in treating inflammatory conditions, he wrote to Dufy, explained the potential benefits and risks of participating in a clinical study of cortisone, and offered to admit him to his research unit in a Boston hospital should he decide to participate.
Having suffered from RA from his early youth, Dufy became increasingly disabled, could not stand without help, and struggled to paint, using only his left hand after losing the use of his right. (He had been unable to hold a brush for years; he had to attach it to his hand with tape.) Despite treatment with gold salts—the standard of the day—he continued to suffer severe flares that forced him to use crutches and finally a wheelchair. His work deteriorated markedly as a result of his illness.
Dufy accepted Homburger’s offer and was admitted to Jewish Memorial Hospital in Boston in April 1950. After initial evaluation and treatment for gingivitis and poor dental health, he began receiving daily cortisone injections in dosages of 100 milligrams. Later, he was put on oral cortisone with buffered aspirin. To blunt the hormone’s side effects, he was prescribed potassium supplements to counteract fluid retention and weekly testosterone to prevent osteoporosis, according to the medical standards of the time. (He was a heavy smoker and drinker, two habits that also promote bone loss.)
Despite fluid retention and stomach disturbances, Dr. Homburger noted that Dufy’s response was “rapid, gratifying, and sustained.” Records from the physiotherapy department showed that by mid-June, Dufy was able to resume many activities of daily living, which had been impossible on admission. Soon he could squeeze his paint tubes unassisted.
Dufy’s joy in his progress was so great that his doctors suspected elevated mood due to the medication, but Berthe, his art dealer and lover, insisted that this was his “old self.” She reported, too, that his libido had returned. With such improvement, a restless Dufy was released from the hospital to a hotel on the banks of the Charles River to paint. His daily cortisone dosage was reduced to 50 milligrams. Despite severe symptoms of toxicity—such as swelling of the face—he was now able to walk and paint for two to three hours a day.
In December 1950, Dufy developed an abscess in the left buttock at the site of his cortisone injections. Because of the ongoing hormone regimen, symptoms of infection were masked until the abscess became very large and Dufy began to show systemic signs: lassitude, malaise, and loss of appetite. Under anesthesia, more than 800 milliliters of pus were drained. Cortisone therapy continued.
On March 12, 1953, Dufy wrote in his last letter to Dr. Homburger, “I had an intestinal episode which appeared to take the form of an obstruction, today completely relieved. But I cannot help but feel a little disturbed about the future and will proceed henceforth with all precautions and remedies necessary.”
Less than two weeks later, at the age of seventy-six, Raoul Dufy died from a massive intestinal hemorrhage, most likely a complication from his three years of continuous treatment with cortisone (and aspirin).
THE HISTORY OF STEROIDS
The story of cortisone is synonymous with Dr. Philip Showalter Hench, of the Mayo Clinic in Rochester, Minnesota. In April 1949, Hench shared startling images of patients with RA; all had recovered with synthetic cortisone. His discovery was hailed as a genuine miracle cure. The following year, Hench and his associate, Edward Kendall, received a Nobel Prize for “discoveries relating to the hormones of the adrenal cortex, their structures and biological effects.”
As the most powerful anti-inflammatory agent yet discovered, cortisone transformed the practice of rheumatology almost overnight. It also revolutionized ophthalmology, gastroenterology, respiratory medicine, dermatology, and nephrology (kidney disorders), and facilitated two remarkable postwar therapeutic developments: organ transplantation and treatment of childhood cancers.
Cortisone and its derivatives, now collectively known as steroids (or corticosteroids), remain among the top ten most widely used prescription and over-the-counter (OTC) drugs. They remain the most powerful anti-inflammatory agents known, and their significance in general medicine is beyond dispute. The number of patients treated with them and their range of clinical applications exceed those of all other medications. It is not surprising that steroids are included in the World Health Organization’s Model List of Essential Medicines.
Millions of new prescriptions for oral steroids are written each year in the United States alone. An estimated 1.2 percent of the US population over the age of twenty—more than 2.5 million people—received oral steroids between 1999 and 2008. While significant, these numbers fall short of total corticosteroid use, as many more people are taking these drugs by topical application and inhalation.
Given practically any disease of unknown cause for which there is no effective treatment, physicians will often put patients on a trial of cortisone to see what happens. The simple convenience of writing a prescription for a steroid has supplanted the traditional scientific method of first understanding a disease and then developing an effective treatment for it.
STEROID DRUGS
Hormones produced by the adrenal cortex (the outer layer of the adrenal gland) consist of four carbon rings linked to form what chemists call the steroid nucleus. Variations on this molecular theme result in drugs with greater or lesser anti-inflammatory potency and more or less of the undesirable effects of salt and water retention.
In 1955, prednisone was introduced into clinical medicine as the first synthetic steroid drug, and three years later, triamcinolone was patented. Prednisone is about five times stronger than cortisone but has the same salt-and water-retaining properties. Triamcinolone is as powerful as prednisone but has less propensity for salt and water retention. When triamcinolone is dissolved in acetone, the resultant triamcinolone acetonide (Trianex, Triesence, Triderm) is very potent and, as a fat-soluble compound, is easily absorbed through the skin, making it the preferred topical steroid in creams and lotions for dermatitis and psoriasis. Intramuscular injection of triamcinolone is sometimes used to control allergic asthma, severe contact dermatitis, seasonal allergic rhinitis (hay fever), and transfusion and drug hypersensitivity reactions (serum sickness). In 2014, the US Food and Drug Administration (FDA) allowed over-the-counter sale of triamcinolone acetonide in nasal spray form under the brand name Nasacort.
Triamcinolone joint injections (Kenalog) for osteoarthritis and RA offer rapid pain relief, usually within twenty-four to forty-eight hours. Improvement lasts six to twelve weeks on average, and injections can be done safely two to three times a year. (In my experience, their efficacy lessens over time.)
HOW STEROIDS WORK: A DOUBLE-EDGED SWORD
Although inflammation can be troublesome, it is actually the cornerstone of our healing system—the body’s way of getting more nourishment and more immune activity to an area that is injured or under attack by germs or toxins. The body regulates inflammation carefully: too little creates susceptibility to infection; too much causes tissue damage and increases risks of allergy and autoimmunity. The twin adrenal glands and the hypothalamus and pituitary in the brain produce very potent hormones that regulate the inflammatory response as well as general metabolism, bone and muscle health, and heart, liver, and kidney function. These hormones also strongly influence our mental and emotional life.
Steroids, either produced in the body or taken as medication, bind tightly to glucocorticoid receptors present in virtually all cells in the human body. This interaction then regulates gene expression in the cell nucleus, suppressing inappropriate inflammation in many tissues and organs: for example, in joints, where inflammation causes RA; in nerves, where it leads to neurological disorders; or in the airways, where it causes asthma. The most important effects of steroids result from these genomic mechanisms. They occur at all dosages, even very small ones (low-dose therapy), and they happen relatively slowly—it may take up to eighteen hours for steroids to take genomic effect.
But at higher doses, non-genomic effects come into play rapidly—over seconds or minutes—resulting from direct interactions with biological membranes. These interactions influence nerve function in the brain, affecting hormone production, behavior, and cognition. This is an important distinction, because the relative potencies of various steroids are completely different in terms of producing non-genomic versus genomic effects.
USES OF STEROIDS
Steroids can be lifesaving in cases of allergic (anaphylactic) shock and other severe allergic reactions, in the treatment of autoimmune diseases, in cases of brain swelling, in cancers of the blood and lymphatic system, and in transplant medicine to prevent rejection of donor organs. In these instances, their worth as immunosuppressant and anti-inflammatory agents is undisputed. But steroids are now used for a great many other conditions, some of them far from serious—like minor cases of dermatitis from contact with poison oak and ivy, diaper rash, and ordinary aches and pains. It is not a good idea to use such powerful drugs for routine complaints. Most people who use steroids do not understand how they work and how dangerous they can be.
When initiating steroid treatment, experts agree on using the smallest dose for the shortest time. Criteria for effectiveness and ineffectiveness of treatment must be defined at the outset, so that treatment can be stopped if it is not helping. Typical doses of prednisone (or its equivalent) are as follows:
• Low dose: less than 7.5 milligrams per day
• Medium dose: 7.5 milligrams to 30 milligrams per day
• High dose: more than 30 milligrams per day
Bear in mind that even small doses of steroids (less than 5 milligrams daily) may cause problems.
THE PROBLEMS WITH STEROIDS
Dose, duration, route of administration, and form of the steroid all influence the frequency and severity of adverse events, as do the patient’s condition and medical history. In 1950, at the age of seventy-three, Raoul Dufy was the oldest patient ever to be treated with cortisone. His age, smoking, drinking, and daily aspirin use all increased his susceptibility to steroid toxicity. He suffered from salt and water retention, facial swelling (often referred to as “moon face,” occurring as a result of redistribution of body fat), infection, mood disturbance, and chronic stomach irritation that led to a fatal gastrointestinal bleed.
Common adverse effects of oral steroids include the following:
acne
blurred vision
cataracts or glaucoma
depression
difficulty sleeping
high blood pressure
increased appetite and weight gain
increased growth of body hair
lowered resistance to infection
muscle weakness
nervousness and restlessness
osteoporosis
sudden mood swings
swollen, puffy face
thinning of skin and easy bruising
worsening of diabetes
Adverse effects are less frequent with steroid injections but can include these:
allergic reactions
bleeding into the joint
infection at the site of injection
skin discoloration
weakening of bone, ligaments, and tendons (from frequent, repeated injections into the same area)
Between 1997 and 2014, the FDA received reports of ninety serious neurologic events, some fatal, related to epidural injection of steroids—a procedure commonly performed to manage neck and back pain. In 2014, the FDA issued a class warning that “safety and effectiveness of epidural administration of corticosteroids have not been established.”
Inhaled steroids, widely used for management of asthma, have fewer adverse effects than oral steroids, but they can cause hoarseness and promote fungal infection of the mouth and throat (thrush). Rarely, prolonged use of inhaled steroids in high dosage will cause the same systemic toxicity seen with long-term oral steroid therapy.
Topical steroids can have local or, rarely, systemic side effects. The stronger the medication, the larger the area to which it is applied, and the longer it is used, the more likely that adverse effects will occur. Young children and the elderly are more susceptible, because they tend to have thinner skin. Topical steroids can cause these side effects:
acne or worsening of existing acne
burning, stinging, or irritation of the skin
excessive hair growth
inflamed hair follicles
rosacea
stretch marks
thinning of the skin
worsening of a preexisting skin infection
One other concern: because steroids suppress symptoms of disease rather than treating root causes, long-term use may strengthen disease patterns and encourage their spread to other sites. For example, suppression of allergic dermatitis in children with long-term topical steroid treatment may increase the risk of later development of asthma. Autoimmune diseases typically wax and wane and have a high potential to go into remission. Long-term immune suppression with steroids may decrease the likelihood of remission. In other words, steroids provoke powerful homeostatic reactions, natural processes aimed at maintaining consistent conditions internally. This pattern can lead to tolerance—the need for larger doses over time—and stubborn dependence that encourages persistent use. Long-term use of steroid drugs is always associated with adverse effects, many of them quite serious.
Perhaps, the most noteworthy fact about steroids is that they are pleiotropic, meaning that they have multiple effects on diverse biological functions. Doctors prescribe them and people take them to alleviate symptoms caused by excessive or misdirected inflammation, but they also suppress immunity in general, increasing susceptibility to infection and retarding wound healing. Over time they regularly cause adverse effects in many systems, from irritation of the stomach to loss of bone density and disturbances of mood.
Sudden discontinuance of steroid therapy or too-rapid lowering of dose usually results in immediate return of symptoms, often worse than before the start of therapy. Because of the homeostatic rebound problem, one should never stop steroid treatment abruptly or decrease the dose too quickly. The weaning process must be slow, and should start only after other measures are in place, such as dietary change and use of natural anti-inflammatory agents. Of course, nonsteroidal anti-inflammatory drugs (like aspirin and ibuprofen) are available as alternative medications, but these have their own drawbacks with long-term use (see chapter 8).
Oral prednisone tablets, 5 to 60 milligrams per day, cost less than $25, with similar figures for oral methylprednisolone (Solu-Medrol) and triamcinolone. Despite the low price of oral steroids, costs associated with adverse effects can be a significant component of the total cost of treatment with these drugs.
INTEGRATIVE MEDICINE APPROACHES TO MANAGING INFLAMMATORY DISORDERS
Integrative medicine offers a number of strategies for managing unwanted inflammation and misdirected immunity, beginning with dietary change.
The body synthesizes substances that regulate inflammation from essential fatty acids (those we cannot make and must get from dietary sources). In general, the omega-6 fatty acids that are found in seeds, grains, nuts, and vegetable oils are the precursors of substances that increase inflammation, while the omega-3 fatty acids, found mostly in oily fish, are the precursors of substances that tamp it down. We need both kinds of fatty acids in the right proportions to keep the inflammatory process in balance. Too little inflammation leaves us susceptible to infection; too much pushes us toward allergy, autoimmunity, and all the diseases associated with excessive, purposeless inflammation. The mainstream diet is top heavy in omega-6s from the refined vegetable oils used in processed foods, and deficient in omega-3s. Correcting this imbalance—by decreasing intake of processed foods and increasing intake of cold-water oily fish and supplemental fish oil—can make a big difference in inflammatory status.
The mainstream diet promotes inflammation in other ways, too: it gives us quick-digesting forms of carbohydrates and not enough of the protective elements found in fruits, vegetables, herbs, and spices. Integrative medicine practitioners routinely recommend an anti-inflammatory diet to many patients on steroids. This type of diet avoids processed foods, limits sugar and animal protein (except for fish and high-quality dairy products), makes liberal use of extra-virgin olive oil, and includes fruit in moderation and an abundance of vegetables. Often, these dietary changes are enough to enable patients to begin weaning themselves off steroids.
Nature provides several powerful anti-inflammatory agents that are nontoxic, not suppressive, and safe for long-term use. Chief among them is turmeric (Curcuma longa), the spice that gives its deep yellow color to curry powder and prepared yellow mustard. An impressive body of scientific evidence documents its anti-inflammatory properties. A botanical relative, ginger (Zingiber officinale) is also effective, and the two can be used together. Although both fresh and powdered turmeric and ginger can be added to foods, for medical use, standardized extracts are better. The reishi mushroom (Ganoderma lucidum), used for centuries in traditional Chinese and Japanese medicine, is another effective, natural anti-inflammatory agent. Too woody and bitter to eat, it is best used in the form of extracts, either liquids or capsules. Follow the dosage recommendations on these products.
The brain and nervous system influence immune function and inflammation. This is the subject of a robust field of study known as psychoneuroimmunology. Reducing stress, practicing relaxation techniques, and employing mind-body therapies (hypnosis, guided imagery, mindfulness training) can dramatically impact inflammatory diseases.
Additional nonpharmacological interventions are available to manage symptoms for which steroids are commonly used. Acupuncture and osteopathic manipulative therapy (OMT), for example, can relieve many kinds of musculoskeletal pain. Traditional Chinese medicine is often able to change the course of ulcerative colitis, Crohn’s disease, and other autoimmune conditions. There are safe and effective botanical remedies for common allergies (see chapter 4), as well as simple home remedies for contact dermatitis and other skin problems. (One example: running hot water for a few minutes—as hot as one can tolerate—on the rash of poison oak or ivy will cause the itching to intensify immediately, then subside for a long time; doing this whenever itching begins hastens resolution of the outbreak.)
BOTTOM LINE
Steroids have been the focus of high hopes and heated debate ever since their dramatic effect on rheumatoid arthritis was discovered more than half a century ago. Certainly, they have a secure place in the medical practice of the present and future. But just as certainly, they are widely overused, often for trivial conditions, and often as the sole or principal treatment for problems that could be managed more safely and as effectively by other means. They are routinely used long term, causing dependence and significant toxicity. Save these powerful drugs for serious medical conditions and try to slowly wean off them once improvement occurs by instituting other measures to keep symptoms at bay.