Ototoxicity—The Hidden Menace
 

Part I: Lives in Upheaval

© November 2003 by Neil Bauman, Ph.D.

"Lynn's" passion was flying. She loved her job as a flight attendant. One day she noticed an ingrown toenail. Within a few days it became infected. The Gentamicin¹ her doctor prescribed killed the infection. It also killed the balance system in her ears. Ever since that fateful day in 1994, Lynn has not been able to work or fly. Without warning, an ototoxic drug turned her world upside down.

An ototoxic drug flipped "Ruby's" life upside down too. She explains: "I cannot drive any more. I had to quit my job as it was an hour's drive away. My mental status is now "foggy" at best. I cannot walk in the dark. My life has changed drastically."

"Bert" lost much of his hearing after taking Doxycycline for a urinary tract infection. "Eunice" told me that just taking the Amitriptyline her doctor prescribed for her resulted in "screaming tinnitus."

"Jonathan" described how he lost hearing in one ear after he took a course of Erythromycin. In addition, he experienced hyperacusis, balance problems and "horrific bilateral tinnitus." "Jonathan's" condition appears to be permanent—as this happened five years ago.

Peggy told me, "I was given Atenolol for some little irregular heart beats. Within a few days my perfectly normal ears started to give me all kinds of noise, roaring and muffledness. Within a week, I woke up one morning stone cold deaf in one ear."

In an email to me, "Sam" told how his doctor had prescribed an ointment containing Tobramycin for a sty on his left eyelid. He wrote, "I started using the cream on my left eyelid on Tuesday. At 8:30 the next morning, I lost the hearing in my left ear." In "Sam's" case, the Tobramycin apparently caused sudden hearing loss just 19 hours later—and this was only from using an ointment on his eyelid!

I wish I could say these are only a few isolated incidents, but I'd be lying if I did so. The truth is—side effects of ototoxic drugs are more common than people (doctor's included) imagine. Each year, the side effects of ototoxic drugs disrupt millions of people's lives and leave a trail of upheaval in their wake.

It is not just drugs taken for chemotherapy and life-threatening infections that cause ototoxic reactions, but the little unexpected everyday things too—an ingrown toenail, a sty on your eye, an irregular heartbeat, high blood pressure, and on and on it goes. Whether the ototoxic side effects result from taking an ototoxic drug for a life-threatening malady or for a relatively minor disorder, the results are the same—lives turned upside down.

Scary? You bet it is. Obviously, it's about time we became aware of what drugs are doing to our ears and learn to make wise decisions regarding them.

What Is Ototoxicity?

To many doctors, ototoxicity just means hearing loss or tinnitus. Others consider only drug side effects that affect the inner ear as being ototoxic. However, Stedman's Medical Dictionary¹¹ defines ototoxicity as the "property of being injurious to the ear." Therefore, any side effect of a drug that damages our ears in any way is ototoxic whether it damages the outer, middle or inner ear.

How Common Are Ototoxic Side Effects?

How common are ototoxic side effects? The short answer is, "No one really knows." We apparently only see (and record) the tip of the iceberg. For extremely ototoxic drugs such as Cisplatin (used in the treatment of cancer), virtually everyone that takes this drug ends up with hearing loss. According to some researchers, not a single person escapes its ravages—100% of the people taking Cisplatin damage their ears.⁵ The resulting hearing loss "is usually irreversible (permanent)."⁸

Another very ototoxic class of drugs are the AMINOGLYCOSIDE antibiotics. Researchers estimate that between one and four million Americans receive AMINOGLYCOSIDE antibiotics (such as Gentamicin, Neomycin, Tobramycin) each year.⁷ According to one study, a person has a 25-30% chance of incurring hearing loss from taking any of the AMINOGLYCOSIDES.⁹ Another study pegs the figure at 63%.⁵

This means that between 250,000 and 1,200,000 people (and maybe as high as 2,520,000 people) in the USA incur hearing losses each year from taking just this one class of drugs. Add to these figures the untold numbers of people who experience other side effects from taking these same drugs—such as tinnitus, dizziness, vertigo and numerous other cochlear and vestibular (balance) problems—and you have a figure of alarming proportions. It is even more alarming when you realize we are just talking about a handful of ototoxic drugs in 2 of the more than 150 classes of ototoxic drugs!

Ototoxic Drugs are Everywhere!

There are at least 743 drugs that are known to be ototoxic.⁴ Here are just 84 of them. This gives an inkling of just how all-pervading ototoxic substances are in the medications we take without having a clue that these drugs may be harming our ears.

• ACE INHIBITORS such as Enalapril (Vasotec),² Moexipril (Univasc), Ramipril (Altace)
  
  
• ACETIC ACIDS such as Diclofenac (Voltaren), Etodolac (Lodine), Indomethacin (Indocin), Ketorolac (Toradol)
  
  
• ALPHA BLOCKERS such as Doxazosin (Cardura)
  
  
• AMINOGLYCOSIDES such as Amikacin (Amikin), Gentamicin (Garamycin), Kanamycin (Kantrex), Neomycin (Neosporin), Netilmicin (Netromycin), Streptomycin, Tobramycin (Tobradex)
  
  
• ANGIOTENSIN-2-RECEPTOR ANTAGONISTS such as Eprosartan (Teveten), Irbesartan (Avapro)
  
  
• ANTI-ARRHYTHMIC DRUGS such as Flecainide (Tambocor), Propafenone (Rythmol), Quinidine (Cardioquin), Tocainide (Tonocard)
  
  
• ANTI-CANCER DRUGS such as Buserelin (Suprefact), Carboplatin (Paraplatin), Cisplatin (Platinol), Vinblastine (Velban), Vincristine (Oncovin)
  
  
• ANTI-CONVULSANT DRUGS such as Carbamazepine (Tegretol), Divalproex (Depakote), Gabapentin (Neurontin), Tiagabine (Gabitril), Valproic acid (Depakene)
  
  
• ANTI-MALARIAL DRUGS such as Chloroquine (Aralen), Mefloquine (Lariam), Quinine (Legatrin)
  
  
• ANTI-RETROVIRAL PROTEASE INHIBITORS such as Cidofovir (Vistide), Ganciclovir (Cytovene), Ritonavir (Norvir)
  
  
• BENZODIAZEPINES such as Diazepam (Valium), Estazolam (ProSom), Midazolam (Versed)
  
  
• BETA-BLOCKERS such as Atenolol (Tenormin), Betaxolol (Betoptic), Metoprolol (Lopressor)
  
  
• BICYCLIC ANTI-DEPRESSANTS such as Venlafaxine (Effexor)
  
  
• CALCIUM-CHANNEL-BLOCKERS such as Diltiazem (Cardizem), Nifedipine (Adalat), Nisoldipine (Sular)
  
  
• COX-2 INHIBITORS such as Celecoxib (Celebrex), Rofecoxib (Vioxx)
  
  
• H1-BLOCKERS such as Cetirizine (Zyrtec), Fexofenadine (Allegra)
  
  
• IMMUNOSUPPRESSANT DRUGS such as Cyclosporine (Neoral), Muromonab-CD3 (Orthoclone OKT3), Tacrolimus (Prograf)
  
  
• LOOP DIURETICS such as Ethacrynic acid (Edecrin), Furosemide (Lasix), Torsemide (Demadex)
  
  
• MACROLIDE ANTIBIOTICS such as Clarithromycin (Biaxin), Erythromycin (Eryc)
  
  
• OPIATE AGONIST DRUGS such as Codeine (Codeine Contin), Hydrocodone (Vicodin), Tramadol (Ultram)
  
  
• PROPIONIC ACIDS such as Flurbiprofen (Ansaid), Ibuprofen (Motrin), Naproxen (Anaprox)
  
  
• PROTON PUMP INHIBITORS such as Esomeprazole (Nexium), Lansoprazole (Prevacid), Rabeprazole (Aciphex)
  
  
• QUINOLONES such as Ciprofloxacin (Cipro), Ofloxacin (Floxin), Trovafloxacin (Trovan)
  
  
• SALICYLATES such as Aspirin, Mesalamine (Asacol), Olanzapine (Zyprexa)
  
  
• SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) such as Fluoxetine (Prozac), Fluvoxamine (Luvox), Sertraline (Zoloft)
  
  
• SEROTONIN-RECEPTOR AGONISTS such as Almotriptan (Axert), Naratriptan (Amerge), Sumatriptan (Imitrex)
  
  
• THIAZIDES such as Bendroflumethiazide (Corzide), Indapamide (Lozol)
  
  
• TRICYCLIC ANTI-DEPRESSANTS such as Amitriptyline (Elavil), Clomipramine (Anafranil)
   

Ototoxic Side Effects

Ototoxic side effects can damage our ears in many different ways. You may experience one, several or no side effects from taking any given drug. The average ototoxic drug exhibits about 3.5 ototoxic symptoms.⁴ Here are a number of the ototoxic side effects you could experience.

When you know which ototoxic side effects can occur, you can watch for them. If they do occur, immediately contact your physician, stop taking the offending drug (with your doctor's consent—of course) to try to limit the damage to your ears.

1. Cochlear side effects

• Tinnitus: Tinnitus, commonly called "ringing in the ears," is the number one indicator that you may be damaging your ears from an ototoxic drug. At least 447 drugs are known to cause tinnitus.⁴ Tinnitus can manifest itself as a wide variety of sounds. It may be a ringing, roaring, beating, clicking, banging, buzzing, hissing, humming, blowing, chirping, clanging, sizzling, whooshing, rumbling, whistling or dreadful shrieking noise in your head. It may also sound like rushing water, radio static, breaking glass, bells ringing, owls hooting or chainsaws running.³
  
  
• Hearing loss: More than 230 drugs are known to cause hearing loss.⁴ Hearing loss can range from mild to profound and may be temporary or permanent. One of the insidious things about ototoxic drugs is they generally first destroy hearing in the very high frequencies which are not normally tested (those above 8,000 Hz). Thus, you're not even aware you are losing your hearing until it is too late to do anything about it.
  
  
• Distorted hearing: Some drugs, instead of causing hearing loss (or in addition to causing hearing loss), cause hearing to be distorted so we do not understand some (or much) of what we are hearing.
  
  
• Hyperacusis: Hyperacusis is a condition where normal sounds are perceived as being much too loud. It is as though the body's internal volume control is stuck on "high." At least 38 drugs can cause this condition.⁴
  
  
• Feelings of fullness in your ears: You can experience this feeling for a few reasons. One, because your ears really are blocked by a middle ear infection or by earwax. Two, because your ears feel "blocked" because of sudden hearing loss. Three, exposure to loud sounds can result in a feeling of "fullness" too.
  
  
• Auditory hallucinations: At least 8 drugs can cause you to hear phantom sounds—voices and music that are not there. Another 165 drugs can cause hallucinations, some of which may be of the auditory variety.⁴ Most of these hallucinations seem to be the result of a damaged auditory system rather than the effects of a mental illness.
   

2. Vestibular Side Effects
 

• Dizziness: Dizziness is the most common ototoxic symptom. At least 588 drugs have this ototoxic side effect.⁴
  
  
• Vertigo: Vertigo is the perception of movement (normally a spinning sensation) when the body is really not moving. At least 432 drugs are known to cause vertigo.⁴
  
  
• Ataxia: Ataxia is the loss of your ability to coordinate your muscles properly and can be a result of a damaged vestibular system. As a result you may walk with a staggering gait, just as though you were drunk. At least 288 drugs can cause this side effect.⁴
  
  
• Nystagmus: Nystagmus is abnormal rapid rhythmic back-and-forth involuntary eye movement, usually from side to side. Although technically an eye problem, it fundamentally is the result of a damaged vestibular system. At least 102 drugs can cause this side effect.⁴
  
  
• Labyrinthitis: Labyrinthitis is a catch-all term that simply means something is wrong in your inner ear (cochlear and vestibular systems).
  
  
• Loss of balance/equilibrium disorder: Some drugs cause a person to lose their balance. These terms too, are mostly catch-alls for various kinds of balance conditions.
  
  
• Oscillopsia: Oscillopsia is "bouncing vision." This is the result of damage to the vestibular system such that it no longer works together as the vestibulo-ocular reflex. Oscillopsia can result when your vestibular system in both ears is severely damaged.
  
  
• Emotional problems: When you lose much of your sense of balance, emotional problems such as anxiety, frustration, anger and depression can surface^.7 Your feelings of self-confidence and self-esteem may plummet.
  
  
• Fatigue: Damage to the vestibular system can result in exhaustion, because you now have to consciously work at maintaining your balance.
  
  
• Memory problems: Memory problems can result because areas of your brain that were previously used for thought and memory, must constantly work on keeping you balanced. As a result, you may grope for words, forget what was just said, be easily distracted or have trouble concentrating.
  
  
• Muscular aches and pains: Another seemingly-unlikely result of vestibular ototoxicity are muscle pains due to failure of the vestibulo-spinal reflex (the reflex dictating automatic muscle changes in response to changing movement). If the reflex fails, you have to consciously control it. You may make your muscles rigid as you strain to keep your balance.
  
  
• Nausea: Nausea is a relatively common side effect of vestibular damage that results from your brain's confusion over vestibular sensory inputs.
  
  
• Visual problems: A host of visual problems can result if the vestibulo-ocular reflex (the reflex that stabilizes your eyes in space) is damaged. As a result, you may have trouble reading since everything seems blurry or fuzzy. You may have trouble focusing your eyes—particularly on moving or distant objects.⁶
  
  
• Vomiting: Vomiting is a common result of a damaged vestibular system. Often vomiting and vertigo go together.
  
  
• Vague feelings of unease: Sometimes you can't put your finger on exactly what is wrong, but you feel vaguely uneasy. You may feel that things seem wrong or unreal.⁷ This too, can be a result of a damaged vestibular system.
   

3. Central Nervous System (CNS) Side Effects
 

• Central auditory processing disorder: Sounds may enter our ears and be processed correctly, but these sound signals may be delayed or scrambled after they leave our inner ears. This scrambling can occur as the sound signals are processed by the neuronal networks that make up our auditory nerves, or in various parts of our brains. When this processed sound reaches the conscious levels in our brains where we "hear," we may hear a bunch of gibberish. This is known as a central auditory processing disorder. Several ototoxic drugs/chemicals have this effect.
   

4. Outer/Middle Ear Side Effects
 

• Ceruminosis: Some drugs cause excessive ear wax production. This excess wax can block our ear canals and cause temporary hearing loss.
  
• Ear pain: Medically called otalgia, ear pain is typically the result of middle ear infections. 154 drugs have ear pain associated with their use.⁴
  
  
• Otitis externa; O. media: Otitis is typically an opportunistic infection of the outer (O. externa) or middle (O. media) ear. Many of the drugs listed as having otitis as an ototoxic side effect do not directly cause these conditions. Rather, these infections come in and take over when an opportunity presents itself—i.e. an ototoxic antibiotic killing off the "good bacteria" in the ear canal, leaving it wide open to an opportunistic invasion of "bad bacteria." 138 drugs are associated with otitis.⁴
   

Risk Factors

Some people take ototoxic drugs with seeming impunity. Others take one little dose, and wham—there goes their ears. Why?

The short answer is that we are all different. Each person (patients and professionals) is a unique biological case study! No two are exactly the same. Therefore, it should be no surprise that we vary in our sensitivity to ototoxic drugs.

Researchers have identified a number of factors that increase the risk of our having an ototoxic reaction when taking certain drugs. Here are 20 of the risk factors (in no particular order of importance).

1. You are very young—including unborn children.
   
   
2. You are a senior (over 60 years).
   
   
3. You have certain hereditary (genetic) factors that make you more susceptible than the general population. This is particularly true if you take AMINOGLYCOSIDE antibiotics.
   
   
4. You already have a sensorineural hearing loss, balance problems or some other form of pre-existing ear damage.¹²
   
   
5. You have had previous ear damage (hearing loss) from exposure to excessive noise.
   
   
6. You have problems with your kidneys. For some reason, people with kidney problems have an unusually high incidence of hearing loss, even without drug use.¹⁰
   
   
7. You are extremely sensitive to drugs or have a low tolerance for drugs.
   
   
8. You have had ototoxic reactions to drugs in the past. Not only does the risk increase, but the resulting ototoxic damage has a tendency to be more severe and is more likely to be permanent.⁷
   
   
9. You have previously used ototoxic drugs, or you have taken repeated courses of the same ototoxic drug.
   
   
10. You have taken certain drugs for a long time—especially if you have taken a drug for longer than the manufacturer recommended.
    
    
11. You can be at higher risk if an ototoxic drug is not administered properly—i.e. larger than recommended dose, higher that recommended cumulative dose, faster dose than recommended (injection or intravenous).⁷
    
    
12. You have been given an inappropriate dose—i.e. a child given an adult dose, or an overweight person given a dose based on total weight rather than on lean body weight (especially true if taking an AMINOGLYCOSIDE antibiotic).⁷
    
    
13. You are dehydrated.
    
    
14. You have taken ototoxic DIURETICS at the same time as other ototoxic drugs or if you have used or are using two or more ototoxic and/or nephrotoxic (toxic to the kidneys) drugs at the same time.
    
    
15. You have had previous ear infections.
    
    
16. You are generally in poor health.
    
    
17. You have abnormal laboratory values such as reductions in serum albumin, serum red blood cells, hematocrit, hemoglobin or you have rising serum creatinine levels.⁷
    
    
18. You have had radiation treatments on your head or ear.⁶
    
    
19. You have bacteremia (bacteria in the bloodstream).⁷
    
    
20. You have either eye or proprioceptive (balance) problems. This increases the chances that you will have a more serious result on your life-style if vestibular ototoxicity does occur.⁷

Reduce The Risk-Here's How

You cannot do anything about certain ototoxic risk factors such as your age or your genetic makeup. However, there are still some things you (and your doctor) can do to lessen your risk of having an ototoxic reaction from taking certain drugs.

Here are some things you and your doctor can do.

1. Be aware of the early warning signs of ototoxicity. The are (in order of frequency): you feel dizzy; your ears begin ringing (tinnitus); your existing tinnitus gets worse or you hear a new kind of tinnitus sound; you feel pressure in your ears (unless you have a head cold); your hearing gets worse or begins fluctuating; or you develop vertigo (spinning sensation).
   
   
2. Tell your doctor you are hard of hearing, especially if you have a sensorineural hearing loss and/or suffer from balance problems. Also, let him know if you have tinnitus.
   
   
3. Always discuss possible side effects with your doctor before you begin a new medication.
   
   
4. Follow your doctor's dosage instructions exactly. At the same time, make sure your doctor does not exceed the drug manufacturer's dosage instructions when he prescribes drugs for you.
   
   
5. Use the same pharmacy for all your prescriptions so they will know all the drugs you are taking. That way they can advise you of any known dangerous drug combinations.
   
   
6. Always read the labels on over-the-counter medications and particularly watch for ototoxic side effects.
   
   
7. Drink plenty of fluids so you don't get dehydrated. This is especially important if you have a fever or are taking loop diuretics.
   
   
8. If you have kidney problems, have your health care professionals carefully monitor your kidney function and report abnormalities immediately. Your doctor needs to know how well your kidneys are working before he prescribes various medications.
   
   
9. Avoid taking multiple ototoxic drugs at the same time.
   
   
10. Avoid noisy environments for at least 6 months after you have completed a course of an AMINOGLYCOSIDE antibiotic or platinum compound such as Cisplatin.⁸
    
    
11. If you are beginning treatment with an ototoxic drug such as any of the AMINOGLYCOSIDE antibiotics, LOOP DIURETICS or platinum compounds such as Cisplatin, it is important that you have a baseline high-frequency audiogram done before you begin treatment and then serial high-frequency audiograms (testing those frequencies above 8,000 Hz) during and after drug therapy.
    
    
12. If you have had vestibular (balance) problems from taking any drugs, be very careful not to damage your vestibular system further by taking drugs known to damage your vestibular system.

When you are aware of the many drugs that can damage your ears and the many risk factors that can make you even more susceptible to ototoxic side effects than the general population, you can take steps to protect your precious ears.

You will then be in the position to take control and make informed decisions about your health care. For example, "Joan" takes Celecoxib for her arthritis. When she takes it, her tinnitus gets louder, but her arthritis problems improve. She chooses the tinnitus over the arthritis pain. That is her choice and she is content to live with it.

"Harold," on the other hand, began taking Amitriptyline and soon noticed he had severe tinnitus. He didn't like this one bit and wrote to me for help. I suggested the Amitriptyline may be causing his tinnitus. With his doctor's permission, he stopped taking the drug. Twelve days later, he joyfully reported that his tinnitus went away. That was his choice. He is happy he made it.

When it comes to the health of your ears, you, too, have a choice. Don't let ototoxic drugs flip your world upside down!

(First published in Audiology Online and Healthy Hearing December 1, 2003.)

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Now read Ototoxicity—The Hidden Menace, Part II to learn even more about ototoxic drugs and how you can protect yourself from their nasty side effects. Although written specifically for audiologists, Part II is still easy-to-read, and contains valuable information that will help anyone concerned about ototoxic drugs and their side effects.

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The information in this paper was taken from the second edition of the book Ototoxic Drugs Exposed by the same author. To learn more about ototoxicity in general, or to learn the specific ototoxic side effects of the 743 ototoxic drugs, 30 herbs and 148 chemicals mentioned in this book, get your own copy of Ototoxic Drugs Exposed.

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If you would like to join an information and support E-mail list for people who have damaged their ears from taking ototoxic drugs, type your E-mail address in the box and click on the Yahoo Groups button. (You can unsubscribe at any time.)

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Notes

¹ In this paper, drug classes are in full capitals (ACE INHIBITORS), generic drug names are in bold (Enalapril) and brand names are in italics (Vasotec).

² The brand names listed here are neither more or less ototoxic than any brands of this same generic drug that are not listed. I have simply chosen, more or less at random, one brand as a representative of all the brands available for that generic drug.

References

³ Bauman, Neil. 2002. When Your Ears Ring. Cope With Your Tinnitus. Here's How. Center for Hearing Loss Help. 49 Piston Court, Stewartstown, PA 17363. http://www.hearinglosshelp.com.

⁴ Bauman, Neil. 2003. Ototoxic Drugs Exposed, Second Edition. Center for Hearing Loss Help. 49 Piston Court, Stewartstown, PA 17363. http://www.hearinglosshelp.com.

⁵ Guidelines for the audiologic management of individuals receiving cochleotoxic drug therapy. 1994. American Speech-Language-Hearing Association. 36(3), Supplement No. 12.

⁶ Haybach, Patty J. 1998. Ototoxicity for nurses. http://www.geocities.com/otolithic/ototox.htm.

⁷ Haybach, Patty J. 1999. Balance and hearing: At risk from drugs. Course #170. http://nurse.cyberchalk.com/nurse/COURSES/NURSEWEEK/ NW170/menu.html.

⁸ Kalkanis, James. 2001. Inner ear—Ototoxicity. eMedicine. 2(7). http://www.emedicine.com/ent/topic699.htm.

⁹ Shlafer, Marshal. 2000. Ototoxic drugs. University of Michigan Medical School. http://www-personal.umich.edu/~mshlafer/ototox.html.

¹⁰ Staab, Dr. Wayne J. 1991. The Rexton guide to better hearing. 512 East Canterbury Lane, Phoenix, Arizona 85022.

¹¹ Stedman's Medical Dictionary. 2000. 27^th Edition. Lippincott Williams & Wilkins. Baltimore, Maryland.

¹² Troost, B. Todd, and Melissa A. Walker. 1998. Drug induced vestibulocochlear toxicity. In: Iatrogenic Neurology. Butterworth-Heinman. Boston. http://ivertigo.net/ototoxicity/otvestibular.html.