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.
Morphine may cause serious or life-threatening breathing problems, especially during the first 24 to 72 hours of your treatment and any time your dose is increased. Your doctor will monitor you carefully during your treatment. Your doctor will adjust your dose carefully to control your pain and decrease the risk that you will experience serious breathing problems. Tell your doctor if you have or have ever had slowed breathing or asthma. Your doctor may tell you not to take morphine. Also tell your doctor if you have or have ever had lung disease such as chronic obstructive pulmonary disease (COPD; a group of lung diseases that includes chronic bronchitis and emphysema), a head injury, or any condition that increases the amount of pressure in your brain. The risk that you will develop breathing problems may be higher if you are an older adult or are weakened or malnourished due to disease. If you experience any of the following symptoms, call your doctor immediately or get emergency medical treatment: slowed breathing, long pauses between breaths, or shortness of breath.
Taking certain other medications during your treatment with morphine may increase the risk that you will experience breathing problems or other serious, life-threatening side effects. Tell your doctor if you are taking or plan to take any of the following medications: cimetidine (Tagamet); other narcotic pain medications; medications for anxiety, seizures, depression, mental illness, or nausea; muscle relaxants; sedatives; sleeping pills; or tranquilizers.
Drinking alcohol, taking prescription or nonprescription medications that contain alcohol, or using street drugs during your treatment with morphine increases the risk that you will experience breathing problems or other serious, life-threatening side effects.
Morphine may be habit-forming. Do not take more of it, take it more often, or take it in a different way than directed by your doctor. Tell your doctor if you or anyone in your family drinks or has ever drunk large amounts of alcohol, uses or has ever used street drugs, has overused prescription medications, or if you have or have ever had depression or another mental illness. There is a greater risk that you will overuse morphine if you have or have ever had any of these conditions.
Do not allow anyone else to take your medication. Morphine may harm or cause death to other people who take your medication, especially children. Keep morphine in a safe place so that no one else can take it accidentally or on purpose. Be especially careful to keep morphine out of the reach of children. Keep track of how many tablets, or capsules, or how much liquid is left so you will know if any medication is missing. Dispose of any unneeded morphine capsules, tablets, or liquid properly according to instructions. (See STORAGE and DISPOSAL.)
Swallow the extended-release tablets or capsules whole. Do not split, chew, dissolve, or crush them. If you swallow broken, chewed, crushed, or dissolved extended-release tablets or capsules, you may receive too much morphine at once instead of receiving the medication slowly over time. This may cause serious breathing problems or death. If you are unable to swallow the capsules whole, follow the instructions in the ''HOW should this medication be used?'' section below to dissolve the capsule contents in applesauce.
Morphine oral solution (liquid) comes in three different concentrations (amount of medication contained in a given amount of solution). The solution with the highest concentration (100 mg/5 mL) should only be taken by people who are tolerant (used to the effects of the medication) to opioid medications. Each time you receive your medication, check to be sure that you receive the solution with the concentration prescribed by your doctor. Be sure that you know how much medication you should take and how to measure your dose.
Tell your doctor if you are pregnant or plan to become pregnant. If you take morphine regularly during your pregnancy, your baby may experience life-threatening withdrawal symptoms after birth. Tell your baby's doctor right away if your baby experiences any of the following symptoms: irritability, hyperactivity, abnormal sleep, high-pitched cry, uncontrollable shaking of a part of the body, vomiting, diarrhea, or failure to gain weight.
Your doctor or pharmacist will give you the manufacturer's patient information sheet (Medication Guide) when you begin treatment with morphine and each time you fill your prescription if a Medication Guide is available for the morphine product you are taking. Read the information carefully and ask your doctor or pharmacist if you have any questions. You can also visit the Food and Drug Administration (FDA) website (http://www.fda.gov/Drugs/DrugSafety/ucm085729.htm) or the manufacturer's website to obtain the Medication Guide.
Why is this medication prescribed?
Morphine is used to relieve moderate to severe pain. Morphine extended-release tablets and capsules are only used to relieve severe (around-the-clock) pain that cannot be controlled by the use of other pain medications. Morphine extended-release tablets and capsules should not be used to treat pain that can be controlled by medication that is taken as needed. Morphine 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?
Morphine comes as a solution (liquid), an extended-release (long-acting) tablet, and as an extended-release (long-acting) capsule to take by mouth. The oral solution is usually taken every 4 hours as needed for pain. MS Contin brand extended-release tablets are usually taken every 8or every 12 hours. Morphabond brand extended-release tablets are usually taken every 12 hours. Kadian brand extended-release capsules are usually taken with or without food every 12 hours or every 24 hours. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand.
If you are taking morphine solution, use the dosing cup or syringe that comes with the medication to measure your dose. Be sure that you know how many milliliters of the liquid you should take. Ask your pharmacist if you have any question about how much medication you should take or how to use the dosing cup or syringe.
If you are taking Kadian brand extended-release capsules and you have a gastrostomy tube (surgically inserted feeding tube), ask your doctor or pharmacist how to administer the medication through your tube.
If you are unable to swallow the extended-release capsules (Kadian), you can carefully open a capsule, sprinkle all of the beads that it contains on a spoonful of cold or room temperature applesauce, and swallow the entire mixture immediately without chewing or crushing the beads. Then rinse your mouth with a little water and swallow the water to be sure that you have swallowed all the medication. Do not mix the beads into any other food. Do not save mixtures of medication and applesauce for later.
Your doctor may start you on a low dose of morphine and gradually increase your dose until your pain is controlled. Your doctor may adjust your dose at any time during your treatment if your pain is not controlled. If you feel that your pain is not controlled, call your doctor. Do not change the dose of your medication without talking to your doctor.
Do not stop taking morphine without talking to your doctor. Your doctor may decrease your dose gradually. If you suddenly stop taking morphine, you may experience withdrawal symptoms such as restlessness; teary eyes; runny nose; yawning; irritability; anxiety; sweating; difficulty falling asleep or staying asleep; chills; back, muscle, or joint pain; nausea; vomiting; loss of appetite; diarrhea; stomach cramps; weakness; fast heartbeat; or fast breathing.
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 morphine,
- tell your doctor and pharmacist if you are allergic to morphine, any other medications, or any of the inactive ingredients in the type of morphine product you plan to take. Ask your pharmacist or check the Medication Guide for a list of the inactive ingredients.
- tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications listed in the IMPORTANT WARNING section and any of the following: antihistamines (found in cold and allergy medications); buprenorphine (Butrans, in Suboxone); butorphanol; cyclobenzaprine (Amrix); dextromethorphan (found in many cough medications; in Nuedexta); diuretics ('water pills'); lithium (Lithobid); medications for migraine headaches such as almotriptan (Axert), eletriptan (Relpax), frovatriptan (Frova), naratriptan (Amerge), rizatriptan (Maxalt), sumatriptan (Alsuma, Imitrex, in Treximet), and zolmitriptan (Zomig); mirtazapine (Remeron); nalbuphine (Nubain); pentazocine (Talwin); quinidine (in Nuedexta); 5HT3 serotonin blockers such as alosetron (Lotronex), dolasetron (Anzemet), granisetron (Kytril), ondansetron (Zofran, Zuplenz), or palonosetron (Aloxi); selective serotonin-reuptake inhibitors such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac, Sarafem, in Symbyax), fluvoxamine (Luvox), paroxetine (Brisdelle, Prozac, Pexeva), and sertraline (Zoloft); serotonin and norepinephrine reuptake inhibitors such as desvenlafaxine (Khedezla, Pristiq), duloxetine (Cymbalta), milnacipran (Savella), and venlafaxine (Effexor); tramadol (Conzip, Ulltram, in Ultracet), trazodone (Oleptro); or tricyclic antidepressants ('mood elevators') such as amitriptyline, clomipramine (Anafranil), desipramine (Norpramin), doxepin (Silenor), imipramine (Tofranil), nortriptyline (Pamelor), protriptyline (Vivactil), and trimipramine (Surmontil). Also tell your doctor if you are taking any of the following monoamine oxidase (MAO) inhibitors, or if you have stopped taking them within the past 2 weeks: isocarboxazid (Marplan), linezolid (Zyvox), methylene blue, phenelzine (Nardil), selegiline (Eldepryl, Emsam, Zelapar), and tranylcypromine (Parnate). Many other medications may also interact with morphine, 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 more 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 any of the conditions mentioned in the IMPORTANT WARNING section or paralytic ileus (condition in which digested food does not move through the intestines). Your doctor may tell you not to take morphine.
- tell your doctor if you have or have ever had a blockage in your stomach or intestines; seizures; difficulty swallowing; prostatic hypertrophy (enlargement of a male reproductive gland); urinary problems; low blood pressure; Addison's disease (condition in which the adrenal gland does not make enough of certain natural substances) or liver, kidney, pancreas, thyroid, or gallbladder disease.
- tell your doctor if you are breastfeeding.
- you should know that this medication may decrease fertility in men and women. Talk to your doctor about the risks of taking morphine.
- if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking morphine.
- you should know that this medication may make you drowsy. Do not drive a car or operate machinery until you know how this medication affects you.
- you should know that morphine may cause dizziness, lightheadedness, and fainting when you get up too quickly from a lying position. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up.
- you should know that morphine may cause constipation. Talk to your doctor about changing your diet or using other medications to prevent or treat constipation while you are taking morphine.
What special dietary instructions should I follow?
Unless your doctor tells you otherwise, continue your normal diet.
What should I do if I forget a dose?
If you are taking morphine tablets or liquid, your doctor will probably tell you to take the medication as needed.
If you have been told to take scheduled doses of the tablets or liquid or if you are taking an extended-release product, take the missed dose as soon as you remember it, and do not take the next dose at your regularly scheduled time. Instead, allow the same amount of time that you usually allow between doses before taking your next dose. If you remember when 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?
Morphine may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:
- stomach pain and cramps
- dry mouth
- mood changes
- small pupils (black circles in the middle of the eyes
- difficulty urinating or pain when urinating
Some side effects can be serious. If you experience any of the following symptoms, call your doctor immediately:
- blue or purple color to the skin
- changes in heartbeat
- 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
- extreme drowsiness
- chest pain
- swelling of the eyes, face, mouth, lips or throat
- difficulty breathing or swallowing
Morphine may cause other side effects. Call your doctor if you have any unusual problems while you are taking this medication.
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).
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). Flush any morphine extended-release tablets, extended-release capsules, and liquid that are outdated or no longer needed down the toilet so that others will not take them. Talk to your pharmacist about the proper disposal of your medication.
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:
- slow, shallow, or irregular breathing
- loss of consciousness
- limp muscles
- cold, clammy skin
- small pupils
- slow heartbeat
- blurred vision
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 morphine.
Before having any laboratory test (especially those that involve methylene blue), tell your doctor and the laboratory personnel that you are taking morphine.
This prescription is not refillable. If you are taking morphine to control your pain on a long term basis, be sure to schedule appointments with your doctor so that you do not run out of medication. If you are taking morphine on a short-term basis, call your doctor if you continue to experience pain after you finish the medication.
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
- Embeda® (containing Morphine, Naltrexone)¶
¶ This branded product is no longer on the market. Generic alternatives may be available.