AUDIENCE: Pharmacy, Internal Medicine, Psychiatry, Neurology, Family Practice
ISSUE: FDA review has found that the growing combined use of opioid medicines with benzodiazepines or other drugs that depress the central nervous system (CNS) has resulted in serious side effects, including slowed or difficult breathing and deaths. Opioids are used to treat pain and cough; benzodiazepines are used to treat anxiety, insomnia, and seizures. In an effort to decrease the use of opioids and benzodiazepines, or opioids and other CNS depressants, together, FDA is adding Boxed Warnings, our strongest warnings, to the drug labeling of prescription opioid pain and prescription opioid cough medicines, and benzodiazepines. See the Drug Safety Communication, available at: http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm, for a listing of all approved prescription opioid pain and cough medicines, and benzodiazepines and other CNS depressants.
FDA conducted and reviewed several studies showing that serious risks are associated with the combined use of opioids and benzodiazepines, other drugs that depress the CNS, or alcohol (see the FDA Drug Safety Communication, available at: http://www.fda.gov/Drugs/DrugSafety/ucm518473.htm, for a Data Summary). Based on these data, FDA is requiring several changes to reflect these risks in the opioid and benzodiazepine labeling, and new or revised patient Medication Guides. These changes include the new Boxed Warnings and revisions to the Warnings and Precautions, Drug Interactions, and Patient Counseling Information sections of the labeling.
FDA is continuing to evaluate the evidence regarding combined use of benzodiazepines or other CNS depressants with medication-assisted therapy (MAT) drugs used to treat opioid addiction and dependence. FDA is also evaluating whether labeling changes are needed for other CNS depressants, and will update the public when more information is available.
BACKGROUND: Opioids are powerful prescription medicines that can help manage pain when other treatments and medicines cannot be taken or are not able to provide enough pain relief. Benzodiazepines are a class of medicines that are widely used to treat conditions including anxiety, insomnia, and seizures.
RECOMMENDATION: Health care professionalsshould limit prescribing opioid pain medicines with benzodiazepines or other CNS depressants only to patients for whom alternative treatment options are inadequate. If these medicines are prescribed together, limit the dosages and duration of each drug to the minimum possible while achieving the desired clinical effect. Warn patients and caregivers about the risks of slowed or difficult breathing and/or sedation, and the associated signs and symptoms. Avoid prescribing prescription opioid cough medicines for patients taking benzodiazepines or other CNS depressants, including alcohol.
Patients taking opioids with benzodiazepines, other CNS depressant medicines, or alcohol, and caregivers of these patients, should seek medical attention immediately if they or someone they are caring for experiences symptoms of unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.
For more information visit the FDA website at: http://www.fda.gov/Safety/MedWatch/SafetyInformation and http://www.fda.gov/Drugs/DrugSafety.
Why is this medication prescribed?
Tramadol is used to relieve moderate to moderately severe pain. Tramadol extended-release tablets and capsules are only used by people who are expected to need medication to relieve pain around-the-clock. Tramadol is in a class of medications called opiate (narcotic) analgesics. It works by changing the way the brain and nervous system respond to pain.
How should this medicine be used?
Tramadol comes as a tablet, an extended-release (long-acting) tablet, and an extended-release (long-acting) capsule to take by mouth. The regular tablet is taken usually with or without food every 4 to 6 hours as needed. The extended-release tablet and extended-release capsule should be taken once a day. Take the extended-release tablet and the extended-release capsule at about the same time of day every day. If you are taking the extended-release capsule, you may take it with or without food. If you are taking the extended-release tablet, you should either always take it with food or always take it without food. Take tramadol exactly as directed. Do not take more medication as a single dose or take more doses per day than prescribed by your doctor. Taking more tramadol than prescribed by your doctor or in a way that is not recommended may cause serious side effects or death.
Your doctor may start you on a low dose of tramadol and gradually increase the amount of medication you take, not more often than every 3 days if you are taking the regular tablets or orally disintegrating tablets or every 5 days if you are taking the extended-release tablets or extended-release capsules.
Swallow the extended-release tablets and extended-release capsules whole; do not split, chew, or crush them.
Tramadol can be habit-forming. Do not take a larger dose, take it more often, or take it for a longer period of time than prescribed by your doctor.
Do not stop taking tramadol without talking to your doctor. Your doctor will probably decrease your dose gradually. If you suddenly stop taking tramadol, you may experience withdrawal symptoms such as nervousness; panic; sweating; difficulty falling asleep or staying asleep; runny nose, sneezing, or cough; pain; hair standing on end; chills; nausea; uncontrollable shaking of a part of your body; diarrhea; or rarely, hallucinations (seeing things or hearing voices that do not exist).
Other uses for this medicine
This medication is sometimes prescribed for other uses; ask your doctor or pharmacist for more information.
What special precautions should I follow?
Before taking tramadol,
- tell your doctor and pharmacist if you are allergic to tramadol or other opiate pain or cough medications any other medications, or any of the ingredients in tramadol tablets, extended-release tablets, or extended-release capsules. Ask your pharmacist for a list of the ingredients.
- tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take. Be sure to mention any of the following: anticoagulants ('blood thinners') such as warfarin (Coumadin, Jantoven); certain antifungal medications such as ketoconazole (Nizoral); cyclobenzaprine (Amrix); dextromethorphan (found in many cough medications; in Nuedexta); digoxin (Lanoxin); erythromycin (E.E.S., E-Mycin, Erythrocin, others); lithium (Lithobid); medications for anxiety, mental illness, nausea, and pain; certain medications for migraine headaches such as almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), sumatriptan (Imitrex), and zolmitriptan (Zomig); medications for seizures such as carbamazepine (Equetro, Tegretol); muscle relaxants such as cyclobenzaprine (Flexeril); promethazine (Phenergan); quinidine; rifampin (Rifadin, Rifamate, Rimactane, others); sedatives; sleeping pills; 5-HT3 receptor antagonists such as alosetron (Lotronex), dolasetron (Anzemet), granisetron (Kytril), ondansetron (Zofran, Zuplenz), or palonosetron (Aloxi); selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), fluoxetine (Prozac, Sarafem), fluvoxamine (Luvox), paroxetine (Paxil, Pexeva), and sertraline (Zoloft); serotonin norepinephrine reuptake inhibitors (SNRIs) such as desvenlafaxine (Pristiq), duloxetine (Cymbalta), milnacipran (Savella), and venlafaxine (Effexor); tranquilizers; and tricyclic antidepressants such as amitriptyline, amoxapine, clomipramine (Anafranil), desipramine (Norpramin), doxepin (Silenor), imipramine (Tofranil), nortriptyline (Aventyl, Pamelor), protriptyline (Vivactil), and trimipramine (Surmontil). Also tell your doctor or pharmacist if you are taking or receiving any of the following medications or have stopped taking them within the past two weeks: monoamine oxidase (MAO) inhibitors such as isocarboxazid (Marplan), linezolid (Zyvox), methylene blue, phenelzine (Nardil), rasagiline (Azilect), selegiline (Emsam, Eldepryl, Zelapar), and tranylcypromine (Parnate). Many other medications may also interact with tramadol, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list. Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
- tell your doctor what herbal products you are taking, especially St. John's wort and tryptophan.
- tell your doctor if you have or have ever had slowed breathing, lung disease, or asthma. Your doctor may tell you not to take tramadol.
- tell your doctor if you have or have ever had seizures; an infection in your brain or spine; a head injury, a brain tumor, a stroke, or any other condition that caused high pressure inside your skull; difficulty urinating; depression; thoughts about harming or killing yourself or planning or trying to do so; mental illness; or kidney or liver disease. Also tell your doctor if you drink or have ever drunk large amounts of alcohol, use or have ever used street drugs, or have overused prescription medications.
- tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking tramadol, call your doctor.
- you should know that this medication may decrease fertility in men and women. Talk to your doctor about the risks of taking tramadol.
- if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking tramadol.
- you should know that this medication may make you drowsy and may affect your coordination. Do not drive a car or operate machinery until you know how this medication affects you.
- you should know that drinking alcohol or using street drugs during your treatment with tramadol increases the risk that you will experience serious, life-threatening side effects. Talk to your doctor about the risks of drinking alcohol or using street drugs during your treatment.
- you should know that tramadol may cause dizziness, lightheadedness, and fainting when you get up from a lying position. To avoid this, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.
- if you have phenylketonuria (PKU; an inherited condition in which a special diet must be followed to prevent mental retardation, you should know that the orally disintegrating tablets contain aspartame, a source of phenylalanine.
What special dietary instructions should I follow?
Talk to your doctor about drinking grapefruit juice while you are taking this medication.
What should I do if I forget a dose?
If your doctor has told you to take tramadol regularly, take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.
What side effects can this medication cause?
Tramadol may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:
- difficulty falling asleep or staying asleep
- uncontrollable shaking of a part of the body
- muscle tightness
- changes in mood
- heartburn or indigestion
- dry mouth
Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately or get emergency medical treatment:
- difficulty swallowing or breathing
- swelling of the eyes, face, throat, tongue, lips, hands, feet, ankles, or lower legs
- agitation, hallucinations (seeing things or hearing voices that do not exist), fever, sweating, confusion, fast heartbeat, shivering, severe muscle stiffness or twitching, loss of coordination, nausea, vomiting, or diarrhea
- nausea, vomiting, loss of appetite, weakness, or dizziness
- inability to get or keep an erection
- irregular menstruation
- decreased sexual desire
- changes in heartbeat
- loss of consciousness
If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).
Tramadol may cause other side effects. Tell your doctor if you have any unusual problems while you are taking this medication.
What should I know about storage and disposal of this medication?
Keep this medication in the container it came in, tightly closed, and out of reach of children. Store it at room temperature and away from excess heat and moisture (not in the bathroom). Keep tramadol in a safe place so that no one else can take it accidentally or on purpose. Keep track of how many tablets or capsules are left so you will know if any are missing.
Unneeded medications should be disposed of in special ways to ensure that pets, children, and other people cannot consume them. However, you should not flush this medication down the toilet. Instead, the best way to dispose of your medication is through a medicine take-back program. Talk to your pharmacist or contact your local garbage/recycling department to learn about take-back programs in your community. See the FDA's Safe Disposal of Medicines website (http://goo.gl/c4Rm4p) for more information if you do not have access to a take-back program.
In case of emergency/overdose
In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.
Symptoms of overdose may include the following:
- decreased size of the pupil (the black circle in the center of the eye)
- difficulty breathing
- extreme drowsiness
- coma (loss of consciousness for a period of time)
- slowed heartbeat
- muscle weakness
- cold, clammy skin
What other information should I know?
Keep all appointments with your doctor and laboratory. Your doctor may order certain lab tests to check your body's response to tramadol.
Before having any laboratory test (especially those that involve methylene blue), tell your doctor and the laboratory personnel that you are taking tramadol.
Do not let anyone else take your medication. Ask your pharmacist any questions you have about refilling your prescription.
It is important for you to keep a written list of all of the prescription and nonprescription (over-the-counter) medicines you are taking, as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this list with you each time you visit a doctor or if you are admitted to a hospital. It is also important information to carry with you in case of emergencies.
Brand names of combination products
- Ultracet® (containing Acetaminophen, Tramadol)
¶ This branded product is no longer on the market. Generic alternatives may be available.