- Tramadol: 7 things you should know
- 3. Downsides
- Study shows tramadol has no effect on osteoarthritis pain scores
- Side effects
- Who should not take tramadol
- Tramadol for dogs and cats
- The Effects of Tramadol Use
- Is Tramadol Harmful?
- Short-Term Effects of Tramadol
- Side Effects of Tramadol
- Long-Term Effects of Tramadol
- Tramadol Dependence
- Tramadol Withdrawal Treatment
- An Athlete’s Reality
- The Big Picture
- More Evidence Against Tramadol
- Fighting Opioid Addiction
- More on Tramadol
- Tramadol – Top 8 Things You Need to Know
- 1. Tramadol is now a controlled substance in all 50 U.S. states
- 2. Tramadol is associated with a wide array of side effects
- 3. Dangerous metabolism, drug interactions with tramadol
- 4. Tramadol can be habit-forming
- 5. What is an Opioid Analgesic REMS?
- 6. Tramadol is available in both immediate-release and extended-release formulations.
- 7. Special populations: the elderly, kidney or liver disease, and pregnancy.
- 8. There are ways to engage with other patients using tramadol.
- Further information
- More News Resources
- Tramadol vs. Oxycodone: Comparison of Side Effects and Effectiveness
- CLINICAL PHARMACOLOGY
- Mechanism Of Action
- Special Populations and Conditions
- Clinical Trials
- Study Results
- Detailed Pharmacology
- Dependence Liability
- Related posts:
- CLINICAL PHARMACOLOGY
Tramadol: 7 things you should know
If you are between the ages of 18 and 60, take no other medication or have no other medical conditions, side effects you are more likely to experience include:
- A headache, nausea, dizziness, constipation, vomiting, joint pains, dry mouth, sweating, and an itchy skin are commonly reported side effects.
- Sedation, which may affect a person’s ability to drive or operate machinery, or perform hazardous tasks is also commonly reported. Alcohol may enhance this effect.
- May cause dependence, addiction, and slowed breathing. Tramadol may be misused and sought after by drug abusers. Tolerance may develop to its effect.
- Seizures have been reported with tramadol use. The risk is increased in people taking certain types of antidepressants (such as SSRIs, SNRIs, TCAs, MAO inhibitors), other opioids, antipsychotics, other drugs that reduce the seizure threshold, with a pre-existing seizure disorder, head trauma, excessive alcohol use, or with a metabolic disorder predisposing to an increased risk of seizures.
- Do not take tramadol if you are also using alcohol, drugs with sedative properties, or other narcotic medications; dangerous or fatal side effects, such as slowed breathing, can occur.
- Seniors over the age of 65 years may be more sensitive to the side effects of tramadol. Tramadol should be initiated cautiously, and extended-release tramadol is best avoided.
- May not be suitable for some people including those with a history of depression or prone to addiction. Tramadol may increase the risk of suicidal thoughts or behaviors.
- Tramadol may not be appropriate for people at risk for respiratory depression, with head trauma, increased intracranial pressure, or with an acute abdominal disease.
- The dosage of tramadol may require adjusting in liver or kidney disease.
- Withdrawal symptoms (such as anxiety, sweating, insomnia, nausea, diarrhea, pain, piloerection ) have been reported when tramadol has been abruptly stopped following dosing for extended periods of time. The dosage of tramadol should always be tapered off slowly on discontinuation.
- Tramadol may interact with a number of other drugs including antidepressants, antipsychotics, St John’s Wort, bupropion, triptans, or other drugs that are metabolized by CYP 2D6 or CYP3A4 hepatic enzymes.
- The metabolism of tramadol may be slowed by people who are poor metabolizers at CYP 2D6. While concentrations of tramadol may be higher in these people, concentrations of the active metabolite of tramadol may be lower, resulting in insufficient pain relief.
- Interaction or overdosage may cause serotonin syndrome (symptoms include mental status changes ), fast heart rate, dizziness, flushing, muscle tremor or rigidity and stomach symptoms (including nausea, vomiting, and diarrhea).
- Rarely, anaphylaxis (a potentially fatal allergic reaction) has occurred with tramadol use, usually following the initial dose. Itchy skin, a rash, difficulty breathing, and other allergy-type symptoms may be more common. Do not use in people with a history of an allergic reaction to codeine or another opioid.
- Tramadol is not FDA-approved for use in children under the age of 12 (immediate-release capsules) or 18 (extended-release capsules).
Notes: In general, seniors or children, people with certain medical conditions (such as liver or kidney problems, heart disease, diabetes, seizures) or people who take other medications are more at risk of developing a wider range of side effects. For a complete list of all side effects, .
Study shows tramadol has no effect on osteoarthritis pain scores
When researchers attempted to demonstrate measurable effects of tramadol on osteoarthritis pain, they came up empty. (.com)Researchers from the University of Georgia have found that tramadol is ineffective in alleviating signs of pain associated with osteoarthritis in dogs, according to a release from the Morris Animal Foundation (MAF), which funded the study. The research team published their results in the Feb. 15 issue of the Journal of the American Veterinary Medical Association.
“The data shows conclusively that tramadol is not an effective drug in treating the pain associated with arthritis in the dog, despite its common recommendation,” says Steven Budsberg, DVM, MS, DACVS, professor of surgery and director of clinical research at the University of Georgia College of Veterinary Medicine, in the MAF release. “This use of tramadol is a classic example of failing to acknowledge and control for bias when evaluating a potential treatment.”
The team at the University of Georgia, led by Dr. Budsberg, compared the use of tramadol with both a placebo and the nonsteroidal anti-inflammatory drug carprofen in client-owned dogs in a randomized, blinded, placebo- and positive-controlled crossover study, according to the study abstract.
Dogs with osteoarthritis of the elbow or knee were assigned to receive each of the three treatments in a random order, with each treatment arm lasting 10 days. Improvement was measured using vertical impulse, peak vertical force and Canine Brief Pain Inventory scores to assess gait and pain levels. The results showed no improvement when tramadol was given compared to either baseline or placebo. Carprofen was associated with significant improvement in results.
We reached out to several veterinary pain experts who contribute to dvm360 and the Fetch dvm360 conferences for their thoughts on the study. As experts often do, they diverge in their assessment of whether tramadol has a role in veterinary practice going forward.
Opinion No. 1: ‘Why would you use it?’
Dr. Michael PettyMichael Petty, DVM, CVPP, CVMA, CCRT, CAAPM, owner of Arbor Pointe Veterinary Hospital and Animal Pain Center in Canton, Michigan, comes down squarely on the “don’t use it” end of the spectrum. He says veterinary pain experts have known for a number of years that orally administered tramadol doesn’t work well for the treatment or prevention of acute pain, “and those of us with pain practices have suspected for several years that tramadol doesn’t work for chronic pain either,” he continues.
“This is based on personal experience-not always the best measure-and on some pharmacokinetic studies showing that the active metabolite is not detectable in many dogs receiving tramadol, even those receiving several hundred milligrams per dose,” he says. “The study by Budsberg and his colleagues is a good one and underlines that tramadol is not a drug that can be depended on for chronic pain issues.”
Dr. Petty says tramadol is a serotonin reuptake inhibitor, which can help with mood, and this could account for what some people see as a positive result when giving it. But it also has a history of causing serotonin syndrome, even at small doses and upon the first administration to a particular dog or cat.
“You have a drug that is a controlled substance, has the potential for human abuse, has no studies showing it works in either acute or chronic pain, and might kill your patient,” Dr. Petty concludes. “Everyone who wants to prescribe it to a patient needs to imagine the courtroom scenario where you’re trying to defend your decision to use it on an animal that came to harm.”
Opinion No. 2: ‘My patients benefit’
Dr. Dani McVetyLike Dr. Petty, Dani McVety, DVM, founder and CEO of the Lap of Love Veterinary Hospice network, says the study results are not unexpected. “I looked at the study, but I didn’t really have to,” she says. “It’s truly no surprise to me or anyone else who’s been using tramadol for years that it’s not the perfect pain medicine.”
But she says hospice practitioners occasionally need to push the boundaries on medical comfort measures, and for her, tramadol will continue to have a role in managing veterinary pain.
“When I prescribe tramadol, I tell my clients that it’s not used directly for pain reduction, but more like a glass of wine,” she says. “Sometimes you need one; sometimes you need two or three to get calmed down a bit. But if we’re leaning on a very high dose for more than one to two nights, we have a quality of life issue and need to have a separate conversation.”
In other words, Dr. McVety uses tramadol in a limited capacity to get a very specific reaction from the pet: calmness. “Sometimes just reducing the emotional wind-up that occurs with pain is helpful to our clients and their pets,” she says. “This is why we will not stop using this medication, combined with adequate pain relief.”
Opinion No. 3: ‘The jury is still out’
Dr. Ralph HarveyRalph Harvey, DVM, MS, DACVAA, is associate professor of anesthesiology at the University of Tennessee College of Veterinary Medicine. He says trying to understand all the nuances of how living things experience pain-and how various drugs affect that experience-is like trying to answer the question “What is truth?”
“I have a great deal of faith in Budsberg and the validated models he uses,” Dr. Harvey says. “The work he has done is meaningful and useful, while not surprising. But many veterinarians far more well-known and expert than I am continue to advocate for the use of tramadol. And veterinarians continue to have the impression that it’s beneficial.”
When Dr. Harvey gives talks on pain management, he asks participants to raise a hand if they’ve heard experts say there’s little to no evidence supporting the use of tramadol in veterinary patients. Many hands go up. “Then I ask how many of them are using tramadol anyway,” Dr. Harvey says. “And many hands go up or stay up.”
In the pyramid model of evidence-based medicine, Dr. Harvey continues, double-blind placebo-controlled studies such as Dr. Budsberg’s rank higher than the bottom level of expert opinion and clinical impression, which can be clouded by bias and wishful thinking. But still, he believes the jury is out on whether tramadol has value in mitigating the experience of pain in veterinary patients.
The problem, he proposes, lies in thinking of tramadol as an analgesic. “We do better to think of it as an emotion-modifying drug-at least in those animals that produce the right metabolite,” he says. “Dogs are extremely variable in their ability to produce that mu-receptor-binding metabolite. Some dogs do; others don’t.”
Dr. Harvey refers to the work of psychologist Ronald Melzack, who several decades ago presented a theory differentiating between two aspects of pain. The discriminative aspect of pain, Melzack says, is highly localized, specific and sharp-it’s what you would experience if you touched a hot stove. The affective aspect of pain is not how it feels but how it makes us feel-it’s the suffering or emotional component of pain.
“The affect of pain is less distinct and slower to come across, and it degrades engagement with life,” Dr. Harvey says. “It’s what Freud was talking about when he said a man with a toothache cannot be in love.”
Of course, no validated assay exists for the emotional experience of animal pain, so it’s extremely difficult to provide evidence that a drug like tramadol is efficacious in relieving it. Another confounding factor is that tramadol is best used as a complementary therapy, Dr. Harvey says, which muddies the waters in terms of knowing which drug is causing which effect.
“But absence of evidence is not evidence of absence,” Dr. Harvey says. “Our greatest limitation in evaluating pain is our ability to recognize and quantify it, especially when it comes to validated models for the suffering aspect of pain. This is a new frontier we are only just beginning to explore.”
Issues surrounding tramadol use-its status as a controlled substance, the potential for human abuse and diversion, the risk of adverse effects such as serotonin syndrome, and patients’ varied ability to metabolize the drug-must all play a role in an individual veterinarian’s decision to use it or not. But is this study the last word on the subject? No, Dr. Harvey says.
“My impression is that, while I have great respect for this study, the metric is limited to the sensory rather than the emotional component of pain,” he says. “But Dr. Budsberg has elevated the conversation, and this is a rich area for continued discussion.”
Tramadol is a prescription medication used to treat moderate to moderately severe pain. It is sold under the brand name Ultram in the United States, and as Ralivia, Dromodol and other names elsewhere. It is intended to work by changing the way the central nervous system responds to pain.
Tramadol is effective on two fronts: About 20 percent of its painkilling effects come from opioids, and 80 percent from ingredients that inhibit the reuptake of serotonin and norepinephrine, two chemicals in the brain associated with mood and responsiveness to pain, said Dr. Lewis Nelson, a professor of emergency medicine at New York University’s Langone Medical Center.
Because tramadol has less opioid content than other addictive painkillers such as oxycodone, hydrocodone and morphine, “a lot of doctors inappropriately view this as safer,” Nelson told Live Science. But tramadol carries risks: People can still abuse and overdose on tramadol because of its opioid component. Its interaction with serotonin can also affect people taking other serotoninlike drugs, such as antidepressants, he said.
However, tramadol’s opioid and serotonergic effects are important because they allow tramadol to treat both pain and the psychological components of pain, he said.
Researchers first synthesized tramadol in the 1970s, and the Food and Drug Administration approved it for treatment of acute and chronic pain in 1995. The Drug Enforcement Administration identified it as a Schedule IV drug in 2014 to show that tramadol has potential for abuse.
Tramadol is available in several forms: tablet, orally disintegrating tablet, extended-release capsule and extended-release tablet, orally disintegrating tablet and suspension. The extended-release tablets and capsules are prescribed for patients who need round-the-clock pain relief.
Safe dosage of tramadol varies based on the patient and his or her needs. For chronic pain, doctors often prescribe a low dose at first, usually after surgery. Doctors also prescribe tramadol to treat arthritis, fibromyalgia and other chronic pain conditions. According to the National Institutes of Health (NIH), the regular tablet and disintegrating tablet are usually taken with or without food every four to six hours as needed. The extended-release tablet and extended-release capsule should be taken once a day.
Patients should not take a larger dose or take it more often or for a longer period of time than prescribed. The NIH advises that if you miss a dose, take it as soon as you remember, unless it is very close to the time for the next dose. Then, skip the missed dose and continue the regular schedule. The dosage may be increased by the doctor, but should not be increased by the patient.
It is also important not to suddenly stop taking tramadol, according to the NIH. Doing so may cause withdrawal symptoms, such as nervousness, panic, sweating, difficulty falling asleep, runny nose, chills, nausea, diarrhea and hallucinations. Your doctor will likely decrease your dose gradually.
Children younger than 12 should not take tramadol, according to 2017 rules from the Food and Drug Administration (FDA). “Our decision today was made based on the latest evidence and with this goal in mind: keeping our kids safe,” Dr. Douglas Throckmorton, deputy center director for regulatory programs at the FDA’s Center for Drug Evaluation and Research, said in a statement.
As noted, tramadol can interact with drugs that affect serotonin levels, such as antidepressants, sometimes leading to serotonin syndrome, described as uncontrollable shaking, altered mental status, rigidity and high body temperature, Nelson said.
Seizures have been reported both in animals and humans taking tramadol. Seizures can happen even at recommended doses, but are more common if a person misuses or overdoses on the drug, or if tramadol interacts with another drug, especially antidepressants, according to a 2009 study published in the journal Psychiatry.
Common side effects of tramadol include:
- Abdominal problems, such as diarrhea, constipation, nausea, or stomach pain
- Depression, including feelings of sadness and discouragement
- Skin problems, such as itchiness, rash, or sweating
- General aches and pains in the muscles and joints
Some side effects are more rare than others, such as:
- Swollen joints
- Weight changes
- Severe headaches
- Falling down
- Severe cough
Some rare side effects warrant a call to the doctor. These include:
- Blisters under the skin
- Blood in the urine
- Chest pain
- Darker urine
- Numbness in the extremities
- Yellowed eyes or skin
Tramadol is increasingly prevalent as a drug of abuse, possibly because other opioids are becoming difficult to obtain, Nelson said.
People who use tramadol therapeutically can become addicted due to the drug’s opioid component. People who abuse the drug to get high or have hallucinations can also become addicted, Nelson said. If people suddenly stop using the drug, they may experience withdrawal symptoms.
“Withdrawal is miserable,” Nelson said. “So people often don’t allow themselves to withdraw, by continuing to take the drug.”
Deaths from tramadol overdose have increased over the past two decades. Researchers at the Centers for Disease Control and Prevention found that the percentage of overdose deaths involving synthetic opioids, such as tramadol, have increased from 8 percent in 2010 to 18 percent in 2015.
“The continuing rise in death rates related to heroin use and synthetic opioids is of great concern,” said Dr. Larissa Mooney, an assistant clinical professor of psychiatry at the University of California, Los Angeles, and director of the university’s Addiction Medicine Clinic.
Because many prescribers view tramadol as a “safer” opioid than something stronger, such as morphine, patients often ignore dosage instructions or drug interaction warnings. Those abusing the drug build tolerance over time and unsafely increase their dosages so that they can continue to achieve the high.
Tramadol is designed for oral use only, and the tablets should not be crushed for the purpose of inhalation or injection. Snorting the drug increases the intensity of the effect of the drug, but brings it in large doses into the bloodstream. These large doses can cause overdose and increase the risk of adverse side effects, such as seizures. Other serious side effects of snorting tramadol include coma and breathing problems.
If you or someone you know has possibly overdosed, emergency help must be contacted at once. Signs of an overdose can include convulsions or seizures, trouble breathing, irregular breathing, pale or blue lips and skin, and pinpoint pupils in the eyes. Some patients may have decreased awareness or responsiveness to the point of loss of consciousness.
Who should not take tramadol
Patients with a history of drug or alcohol abuse, or a history of suicide attempts should not use tramadol. It should not be taken at the same time as alcohol, street drugs, narcotic pain meds, sedatives or medication used to treat mental illness, according to the Mayo Clinic.
Taking tramadol increases the risk of seizures for those with a history of seizures, a head injury, a metabolic disorder, or those taking antidepressants, muscle relaxers and narcotics. Before taking tramadol, be sure to inform your doctor if you have kidney disease, cirrhosis or other liver disease, a stomach disorder, or a history of depression and mental illness, the Mayo Clinic reports.
It should be used sparingly in the elderly, as they are more likely to have unwanted side effects such as constipation, lightheadedness, dizziness, fainting, and stomach upset, as well as age-related kidney or liver disease.
Tramadol for dogs and cats
For dogs and cats, tramadol is used often as a pain reliever for post-surgery pain or chronic conditions such as cancer or arthritis, said Dr. Greg Nelson, a veterinarian with Central Veterinary Associates, in Valley Stream, New York.
“It’s usually not one of the first things we reach for, but we use it when there’s a little bit more advanced pain after surgery,” Nelson said.
It is also used as a cough suppressant in pets. It’s most often used in dogs, though it can be used for cats as well. (The pill comes in 50-milligram capsules, and cats usually take 10 mg tablets, Nelson said. However, pet owners can ask pharmacists to make special cat-sized dosages, he said.)
Tramadol is used as an alternative or in addition to non-steroidal anti-inflammatory drugs (NSAIDs) or in conjunction with them, Nelson said. Because tramadol works differently than NSAIDs, they can be used as an alternative for pets who cannot take NSAIDs. The tablets can be given to pets with or without food, but dosage instructions from the vet must be followed. Just as in humans, if the medication has been used long term, do not abruptly stop giving it for risk of withdrawal symptoms. Work with your vet to wean your pet off of tramadol properly.
Additional reporting by Alina Bradford, Live Science Contributor.
- National Institutes of Health: Tramadol
- Mayo Clinic: Usage of Tramadol
- Mayo Clinic: Tramadol (Oral Route) Description and Brand Names
- American Kennel Club: Tramadol for Dogs
The Effects of Tramadol Use
Table of Contents Authored By American Addiction Centers Editorial Staff Reviewed By Erik MacLaren, PhD
Tramadol is a synthetic opioid analgesic (painkiller) that is frequently prescribed to manage moderate to severe levels of pain—such as that experienced after surgery or in chronic conditions like arthritis. It is commonly marketed under one of its brand names, Ultram.
People who experience more chronic types of pain may be prescribed an extended-release version of tramadol, which allows them to experience longer lasting pain relief without needing to take the medication as frequently.
Tramadol Effects question 1
Is Tramadol Harmful?
This drug – while somewhat atypical with its activity as an opioid – still elicits its narcotic properties via the brain’s opioid receptors. Similar to other drugs in this class of substances, some people may be at risk for addiction if they:
My pain typically would occur over two or three days. I took one or two a day until it eased. But I noticed on the days I took tramadol I felt more relaxed and coped with life better. Since the doctor had prescribed so many, at least two or three boxes, I started taking one every day….They had come from a doctor, so I was sure they couldn’t harm me…..I didn’t worry whether they were safe or not, I just needed them.
- Use it for a long period of time.
- Take larger doses than recommended.
- Take it more frequently than has been prescribed.
- Take it for non-medical purposes.
- Take it concurrently with other substances, such as alcohol, sedatives or other painkillers.
Addiction is characterized by:
- Compulsive drug seeking behavior.
- An inability to limit use on one’s own.
- Difficulty functioning without the drug.
Tramadol Effects question 2
Treatment Advisors Are On Call 24/7 Who Answers? Thinking About Getting Rehab?
Short-Term Effects of Tramadol
Tramadol works by modifying the processing of pain signals traveling between the nerves and the brain. However, it has several different targets in the nervous system—each imparting contributions to tramadol’s pain relieving and, sometimes, mood altering properties. However, two well-known effects of tramadol are considered to be the most relevant for its ability to relieve pain and encourage abuse.
Don’t let a tramadol addiction control your life. Learn about treatment and recovery today.
First, like heroin, codeine, and all other opiate analgesics, tramadol binds to opioid receptors in the brain and spinal cord. These receptors are responsible for both the pain-relieving effects that patients need and, at higher doses, the euphoric effects that abusers seek.
Because tramadol is much less potent than other commonly abused narcotics when it is injected, it was thought to be a safe alternative to other painkillers like morphine. However, when taken by mouth, tramadol is converted into another compound called O-desmethyltramadol, which is a much more potent activator of opioid receptors than tramadol itself. As a result, users may get high on tramadol, even if that was not their intention when they first started taking the drug.
The second important mechanism of tramadol is that it raises the brain levels of the neurotransmitters serotonin and norepinephrine, similar to antidepressant drugs like venlafaxine (Effexor). Ultram’s effects on serotonin and norepinephrine signaling in the brain is thought to be partially responsible for the drug’s ability to reduce depressive and obsessive-compulsive symptoms in patients taking it. These effects on mood may cause some patients, like the women quoted above, to take tramadol in larger doses and more often than prescribed, putting them on a path to dependence.
Short-term effects of tramadol include:
- Lack of pain. Tramadol is a painkiller; it modifies the transmission of pain signals to the brain so that you experience less intense pain while you are taking it.
- Elated mood. Tramadol works in a similar way to many antidepressant medications in that it increases the levels of serotonin and norepinephrine in your brain. This may lead to feelings of euphoria and well-being. For some individuals, these pleasant symptoms serve to reinforce a pattern of continued tramadol use.
- Anxiety reduction. Tramadol helps some users feel relaxed and calm because of the way it changes brain chemistry.
These symptoms and signs can contribute to a developing tramadol addiction, especially if the individual in question is concurrently experiencing depression and/or anxiety issues.
Tramadol Effects question 3
Tramadol Effects question 4
Side Effects of Tramadol
Some potential side effects of tramadol include:
- Difficulty falling asleep.
- Loss of appetite.
- Dry mouth.
People who have a seizure disorder should consult with their doctor prior to taking tramadol. Tramadol’s effects on various neurotransmitter systems are thought to mediate a potential pro-epileptic response—in other words, this medication may cause seizures. This property also makes tramadol especially dangerous for abusers because the probability of convulsions or seizures increases at high doses.
Other serious reported side effects that require medical attention include:
- Hives, blisters, or rash.
- Difficulty swallowing or breathing.
- Lack of coordination.
- Rapid heartbeat.
Tramadol Effects question 5
Long-Term Effects of Tramadol
An increasing number of practitioners shy away from prescribing Tramadol for long-term use due as knowledge of the undesirable effects that are experienced when this drug is used over a long period of time becomes more common. These effects may vary, but they often include:
- Tolerance: As tramadol works by changing a person’s brain chemistry, there is a risk of developing tolerance to this drug. As the body adapts to tramadol’s presence, users need larger doses of the drug to feel its painkilling and euphoric effects.
- Physical dependence: Along with tolerance, many users experience physical dependence if they use tramadol for a long period of time. Their bodies adapt to the presence of the drug, and soon require tramadol in order to function properly. If a dependent individual stops taking tramadol, they may become physically ill due to the onset of a withdrawal syndrome.
- Cognitive decline: Many opioid drugs are associated with cognitive impairment and slowed reaction times. Complex tasks may become more difficult with long-term use of tramadol, and users may present a danger to themselves or others when driving.
The side effects of tolerance and dependence may ultimately lead to a tramadol addiction. Like other kinds of prescription drug abuse, many individuals struggling with an addiction to tramadol need not obtain their drug from an illicit market to continue their cycle of dependence; they begin taking it as prescribed and then take a larger dose on their own when the medication stops working. People may, at some point resort to methods such as “doctor shopping” or prescription forgery to guarantee an uninterrupted supply of the pharmaceutical they find themselves hooked on.
Those who abuse tramadol for recreational purposes or who have developed tolerance after taking it for some time may take greater doses than recommended and are at increased risk for overdose.
Symptoms of tramadol overdose include:
- Decreased pupil size (pinpoint pupils).
- Slowed breathing.
- Slowed or irregular heartbeat.
- Cold, clammy skin.
Tolerance to the effects of tramadol can develop quite early. At the point that tolerance has occurred, dependency is close to follow. People may experience some degree of physiologic tramadol dependency even if the medication is taken as prescribed. However, the likelihood of a more pronounced dependency increases when taken in doses or on a schedule that deviates from that prescribed.
A tenacious psychological addiction may occur when one begins taking increasing amounts of the medication to overcome tolerance, mitigate the onset of withdrawal or merely using tramadol to get high and otherwise avoid dealing with problems in your life.
Tramadol Withdrawal Treatment
The symptoms of withdrawal can be very unpleasant and, in extreme cases, even dangerous. Many decide to seek help with discontinuing their use of tramadol by first going to a detox center. The process of detoxification allows patients to withdraw from a drug under medical supervision. Doctors may give you other medications or treatments to help you with the physical discomfort you may experience while you withdraw from tramadol.
Effects of withdrawal from tramadol overlap with both opiate and anti-depressant withdrawal syndromes and include:
- Gastrointestinal pain.
- Numbness in the extremities.
- Ringing in the ears.
Many people experience flu-like symptoms such as vomiting and nausea while withdrawing from tramadol. You may also experience tingling in your hands and feet.
After withdrawal is complete, you may want to attend an inpatient program at a rehab center. These types of programs require you to live at the center with other patients, who are also learning to live a new life in recovery—leaving behind the drugs they’ve been struggling with. During rehab, you usually undergo individual and group therapy sessions to help you learn new coping skills and ways of dealing with your emotions, as well as learn techniques to modify previously maladaptive behaviors that may have contributed to your addiction. Your friends and family may also receive therapy to help them process their feelings about how you behaved while in the throes of addiction. In addition, you probably will have the opportunity to attend support groups, like a 12-step program.
Most rehab programs last 30 to 90 days, although they may last longer. Adhering to an aftercare schedule after the initial period of rehab has concluded is beneficial for relapse prevention and long-lasting recovery. Many people continue with outpatient therapy and regular participation in a support group setting at this point. Outpatient approaches to treatment aren’t just for aftercare, however, as some people opt to complete a period of initial addiction treatment. Outpatient programs allow you to return to your normal daily activities while attending therapy sessions at a treatment center.
Tramadol Effects question 6
Last updated on June 11, 2019 2019-06-11T11:00:29+00:00 Finding the perfect treatment is only one phone call away!
The opioid epidemic in the United States and around the world is not a secret, but how much do people really know about the abuse of prescription drugs in sport? Are they aware of how often seemingly innocent prescriptions for oxycodone or tramadol can turn into full-blown addictions? That the addiction can lead to an overdose and death? That it can happen to anyone, even athletes? Especially athletes?
At USADA, we believe that medical advice should come from physicians, but it is within our purview to draw attention to health and safety issues that impact athletes. As such, USADA has publicly provided education and guidance on substances and methods that are on the World Anti-Doping Agency (WADA) Prohibited List, while also pushing for other substances to be added to the List because of associated health risks and performance-enhancing capabilities.
One such drug is the narcotic painkiller tramadol, a still-legal substance in sport that is both powerful and dangerous. USADA, alongside numerous other organizations in the world of sport, believe that the time is now for WADA to finally move the drug from its Monitoring Program (where it has been since 2012) to the Prohibited List, alongside 12 other narcotics that are already banned in-competition.
While USADA and other consulted stakeholders provided substantial evidence about the health risks and abuse of tramadol in sport after WADA requested comment on its inclusion in 2015, WADA has not yet added the drug, which is being abused in at least one sport. According to the WADA Monitoring Program, 71 to 82 percent of the tramadol use between 2012 and 2015 in globally monitored sports occurred in cycling.
Without doubt, tramadol raises legitimate questions about how it should be regulated in sport, as it has both clinical utility and potential for abuse. The debate becomes particularly complex when a drug is associated so closely with a single sport.
However, the enormity of the drug’s threat becomes more apparent when some athletes talk about their experiences with the powerful painkiller.
An Athlete’s Reality
Ian Mullins, an elite mountain bike racer, points out that tramadol is the go-to painkiller for many athletes, especially cyclists, despite its reputation of abuse. Speaking from experience, he explains that athletes feel perceptible pain relief by taking tramadol – a potent painkiller – before, during, and after intense workouts or competitions – all without risking a positive test. Unlike other narcotics, such as oxycodone and morphine, athletes know they can use tramadol whenever the pain hits and still remain compliant with anti-doping rules.
Which is, in large part, how Mullins got addicted to the drug.
He started taking tramadol when his doctor prescribed it to him as pain relief from chronic pancreatitis, but soon realized that he could both train and race better while taking the drug.
“Using tramadol can feel as good as getting a blood transfusion for athletes,” says Mullins. “You can pop a pill 18 hours into a 24-hour endurance race and it’s an immediate boost that helps you power through the end.”
Fortified by recollections of his doctor saying that tramadol-dependency wasn’t something he’d encountered, Mullins started getting tramadol through other routes when his prescription ran out, wanting the pain relief and believing that he wouldn’t get addicted. But before long, his days were consumed by watching the clock, counting down the minutes between doses.
His addiction was obvious – and disturbing – to both himself and those around him. His dependency destroyed a relationship, and it made him wonder how anyone could simultaneously be an addict and an elite athlete who cares about their body.
Trying to break the addiction, he would avoid taking the drug, only to be overcome by the debilitating symptoms of withdrawal, from nausea to cold sweats. This cycle of need and regret was interspersed with a number of overdoses that left Mullins disoriented, bleeding, and desperate for rehabilitation.
“Getting on and off drugs is hell,” Mullins explains. “Psychologically, I knew I was dealing with addiction, but it took me years of physical struggle to break that addiction.”
This left him questioning how something so powerful and so addictive could be allowed in sport. He saw major benefits on the bike thanks to tramadol’s performance-enhancing properties, while also being crushed by it’s addictive nature and side effects, making it a seemingly obvious candidate for the WADA Prohibited List.
“I don’t want any other athletes to go through what I’ve experienced because they think it’s safe to use tramadol just because it’s not banned in sport,” Mullins notes. “My biggest mistake, other than taking tramadol in the first place, was not asking for help to get off it. There isn’t just one way to overcome addiction, but help is there if you ask, and it can save your life.”
Mullins has witnessed enough fellow cyclists experiencing the highs and lows of tramadol use to know that he wasn’t the only one going through the battle against opioid abuse. Knowing this, he contacted USADA and others to share his story in hopes of spreading awareness about the issue plaguing his sport and fellow cyclists.
The Big Picture
It’s not hard to see why athletes might get addicted to tramadol and other pain medications when they are constantly pushing their bodies to the limits. But as USADA’s Science Director Matthew Fedoruk points out, “We often hear from athletes and others that tramadol is being abused in sport. Our job is to ensure that athletes can compete clean and win, and like other narcotics on the WADA Prohibited List, it’s our belief that tramadol abuse threatens athletes’ health and their right to a level playing field.”
To this point, a study by Loraschi et al. (2014) showed that cyclists identified tramadol as a doping agent, meaning that riders clearly understand that tramadol can be used to enhance performance. According to eyewitness reports, tramadol is even handed out freely with water bottles during cycling races to combat late-stage pain.
On the subject of painkiller use in cycling, elite cyclist Taylor Phinney is quoted in Cycling Tips saying, “You have to ask why are you taking a painkiller? You are doing that to mask effects that riding a bike is going to have on your body…essentially, you are taking a painkiller to enhance your performance. But the whole reason we get into sport in the first place is to test our bodies, to test our limits. If you are taking something that is going to boost your performance, that is not exactly being true to yourself, not exactly being true to your sport.”
The 2015 Cycling Independent Reform Commission Report provides further evidence and echoes rider concerns that tramadol has been widely used in the peloton because of its non-banned status and potent PED qualities.
More Evidence Against Tramadol
In addition to performance-enhancing benefits, research suggests that tramadol can have serious side effects, including the potential for decreased alertness, seizures, and addiction. In terms of addiction, a Washington Post-Kaiser Family Foundation survey found that “one-third of Americans who have taken prescription opioids for at least two months say they became addicted to, or physically dependent on, the powerful painkillers.”
Just deemed a Schedule IV controlled substance in 2014, the U.S. Drug Enforcement Administration (DEA) cited that the addictive qualities of tramadol would lead it to be “diverted from legitimate sources, used without medical supervision, and consequently become a safety concern to individuals and the community.” The DEA additionally cites that symptoms of tramadol abuse are similar to other opiates and can include serotonin syndrome, seizures, and stopped breathing. Because of its toxic mechanisms, tramadol use does come with risk of overdose, and the effects range from significant neurologic toxicity, such as coma, to cardiovascular toxicity like tachycardia. Tramadol can also have adverse interactions with other products. For example, the DEA explains that tramadol’s interaction with alcohol can be fatal and that deaths associated with tramadol have been well documented in medical texts.
Dr. Fedoruk also notes that, like many medications, the pharmacological effects and metabolism of tramadol varies between individuals, even when people use identical doses. If overdose does occur, it’s also important to note that medications like Naloxone (Narcan), often used in emergency situations to reverse an opioid overdose, are less effective in treating a Tramadol overdose and reportedly reverses just 30 percent of tramadol’s effects.
Anecdotal accounts also indicate that tramadol use could be at play in pro peloton crashes. For example, Phinney was quoted in CyclingTips saying, “You see so many late-race stupid crashes that I almost wouldn’t be surprised if some or most of those crashes are caused by people taking these hard-hitting painkillers at the end of races.” This point is substantiated by the fact that the tramadol product insert in the U.S. warns, “While taking DO NOT: Drive or operate heavy machinery, until you know how affects you. can make you sleepy, dizzy, or lightheaded.”
In further support of this theme is a Johns Hopkins study referenced in the Wall Street Journal. From analyzing emergency room visits across sub-Saharan Africa, Dr. Ibrahima Amadou discovered that 80 percent of traffic accidents involved a driver on tramadol.
Based on tramadol’s serious health effects, potential for abuse, the many other narcotics on the Prohibited List, and the fact that there are safer non-opioid analgesic alternatives, USADA continues to urge WADA to add tramadol to the Prohibited List. Prohibiting the use of tramadol in sport will both protect athletes and help ensure a level playing field.
Fighting Opioid Addiction
At this point, tramadol abuse appears to be a threat to all athletes, but particularly those in cycling. As such, USADA encourages all athletes to be informed, make healthy decisions, and reach out to us if they need assistance or information.
Outside of USADA, here are some other relevant resources:
- Behavioral Health Treatment Services Locator
Find alcohol, drug, or mental health treatment facilities and programs around the country at findtreatment.samhsa.gov
- Opioid Treatment Program Directory
Find treatment programs in your state that treat addiction and dependence on opioids, such as heroin or prescription pain relievers, at dpt2.samhsa.gov/treatment/
- Suicide Prevention Lifeline
24-hour, toll-free, confidential suicide prevention hotline available to anyone in suicidal crisis or emotional distress. Your call is routed to the nearest crisis center in the national network of more than 150 crisis centers.
- SAMHSA’s National Helpline
Also known as, the Treatment Referral Routing Service, this Helpline provides 24-hour free and confidential treatment referral and information about mental and/or substance use disorders, prevention, and recovery in English and Spanish.
Drug Abuse, The Rise of Tramadol: Exploring the Dangers and Conversations and this Opioid
Cycling Tips, UCI Lobbying WADA to ban Tramadol
Cycling Tips, UCI Frustrations continue as WADA denies request to ban Tramadol
Wall Street Journal, The Painkiller that Cycling Wants to Ban
Wall Street Journal, Tramadol: The Opioid Crisis for the Rest of the World
Regulations.gov, Schedules of Controlled Substances: Tramadol; Schedule IV
Washington Post, Post-Kaiser survey of long-term prescription opioid painkiller users
Washington Post, One-third of long-term users say they’re hooked on prescription opioids
Velo Nation, Taylor Phinney Interview: Getting the pill culture out of the sport
More on Tramadol
Tramadol – Top 8 Things You Need to Know
Medically reviewed by Leigh Ann Anderson, PharmD Last updated on Jan 24, 2020.
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Generic Name: tramadol (TRAM a dol)
Brand Names: ConZip, Ultram
Maybe you’ve heard that tramadol is a “safer” pain medication. But is that really true? Is tramadol a narcotic?
The facts: tramadol is classified as a centrally-acting, oral analgesic (pain drug) that contains an opioid (narcotic). So yes, tramadol is a narcotic. Other opioids include drugs you may be more familiar with, like oxycodone or codeine. Opioids have made headlines over the past few years due to the tremendous problem of opioid addiction in the U.S.
Tramadol is approved for the treatment of pain in adults that is severe enough to require an opioid analgesic and for which other treatments do not work or are not tolerated. Dosing is individual for each patient. The lowest effective dose for the shortest duration should be used.
In addition to acting at the opioid pain receptor, tramadol also inhibits uptake of two neurotransmitters, norepinephrine and serotonin, which may add to its pain-relief effects, although the exact mechanism isn’t exactly known.
In 1995, tramadol was originally approved by the U.S. Food and Drug Administration (FDA) as a non-controlled analgesic. However, since 1995, changes to the controlled substance status of tramadol have been made due to reports of drug abuse, misuse and criminal diversion (shifting of any legally prescribed controlled substance from the patient to another person for any illicit use, such as abuse or sale on the streets).
1. Tramadol is now a controlled substance in all 50 U.S. states
The U.S. Drug Enforcement Administration (DEA) announced that tramadol classification was placed into schedule IV of the Controlled Substances Act (CSA) effective August 18, 2014.
- The new scheduling applies to all forms of tramadol.
- The rescheduling of tramadol came at a time of growing concern related to abuse, misuse, addiction and overdose of opioid analgesics.
- Previously, tramadol was a controlled substance in only a few states.
Tramadol prescriptions in the U.S. may now only be refilled up to five times within a six month period after the date on which the prescription was written. After five refills or after six months, whichever occurs first, a new prescription is required. This rule applies to all controlled substances in schedule III and IV.
Ask your pharmacist how to properly dispose of tramadol or any opioid that you are prescribed.
Learn More: How to Safely Dispose of Your Old Medications
2. Tramadol is associated with a wide array of side effects
In many people, tramadol is well-tolerated when used for pain, but tramadol can also cause some common and serious side effects. In fact, the Drug Abuse Warning Network (DAWN) has reported that over 50,000 emergency department visits were related to tramadol use, and over half of these visits were related to side effects of the drug.
Tramadol has a long list of serious and potentially fatal reactions. It is important to discuss these side effects with your doctor before starting treatment as they can worsen with higher doses or with drug interactions. If you start this drug slowly and at a lower dose as directed by your doctor, it may help to lessen side effects at the start of treatment. Call your healthcare provider if you have any of side effects that are severe or concerning to you.
The most common side effects (≥ 10% to 15%) may include:
- dizziness / vertigo
- nausea, vomiting
- constipation (can be more common in the elderly > 75 years)
- dry mouth
- somnolence, drowsiness
Other common adverse reactions:
- stomach pain, heartburn
- nervousness, anxiety, agitation
- weakness (asthenia)
- decreased appetite
Serious side effects, some of which are rare, may include:
- addiction, abuse, and misuse, which may lead to overdose, coma and death, even at normal doses
- slowed or stopped breathing (respiratory depression), which may be life-threatening or fatal. There is a high risk in those with lung disease, elderly, or a very ill or debilitated state.
- ultra-rapid metabolism (break down of the drug in the body for elimination) of tramadol and other risk factors for life-threatening respiratory depression in children (some cases occurred after tonsillectomy or removal of adenoids)
- neonatal opioid withdrawal syndrome (with prolonged use of tramadol during pregnancy).
- effects due to drug interactions with benzodiazepines or other sedative-type (CNS depressant) drugs, including alcohol or illicit street drugs
- serotonin syndrome (a potentially life-threatening condition)
- suicide or attempted suicide
- occurence or worsening of central sleep apnea
- severe hypotension (low blood pressure)
- gastrointestinal (stomach, intestine) side effects
- risk in patients with increased intracranial pressure, brain tumors, head injury, or impaired consciousness
- abnormal heart rhythms
- severe hypersensitivity (allergic) reactions
- opioid withdrawal
Breathing changes like slowed or stopped breathing can occur at any time with tramadol, but the risk is especially great when treatment is first started (within the first 24 to 72 hours) or when there is a change in your dose. Your doctor may need to adjust your tramadol dose or discontinue treatment based on how it affects your breathing.
Opioids can lead to other breathing problem like central sleep apnea (CSA) and low oxygen in your blood while you are sleeping. These effects may be worse with higher doses. If you have sleep apnea, your doctor may need to adjust your dose of your opioid or find a safer treatment for you.
You should NOT use tramadol if have severe asthma or breathing (respiratory depression) or lung problems, a bowel blockage or narrowing, or an allergy to tramadol. Do not use tramadol if you have taken a monoamine oxidase inhibitor (MAOI), a type of drug for depression, in the last 14 days.
Seizures have occurred in patients taking recommended doses but are more likely at high doses associated with abuse.
Do not abruptly stop taking tramadol as withdrawal symptoms like nausea, diarrhea, anxiety, or tremors may occur. More serious withdrawal symptoms, uncontrolled pain, and suicide may occur in those physically dependent on opioids. Consult with your doctor on how to slowly stop treatment.
Tramadol Warnings: Use in Children
- Life-threatening respiratory depression (difficult, slowed breathing) and death have occurred in children who received tramadol. Accidental ingestion or exposure of tramadol in children, even one dose, can be fatal.
- Tramadol should NOT be used in children younger than 12 years of age (it is contraindicated).
- Tramadol should NOT be used in children younger than 18 years of age after tonsillectomy and/or adenoidectomy surgical procedures (removal of tonsils and/or adenoids).
- Avoid the use of tramadol in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol.
- Risk factors may include: respiratory depression after surgery, obstructive sleep apnea, obesity, severe lung disease, neuromuscular disease, and use of other medications at the same time as tramadol that also cause respiratory depression (slowed or stopped breathing).
Tramadol Warnings: Use in the Elderly
- Respiratory depression is a chief risk of opioid use in the elderly. Doses should be titrated slowly and patients monitored for slowed breathing. Use any form of tramadol with extreme caution in patients 75 years and older.
- The elderly may be especially prone to side effects with tramadol due to lowered liver or kidney function and reduced metabolism or excretion.
- Patients older than 75 years appear to be more prone to gastrointestinal side effects like constipation (30%) than patients less than 65 years (17%).
Other side effects with tramadol can occur. Review a full list of tramadol side effects here.
3. Dangerous metabolism, drug interactions with tramadol
You probably already suspected that tramadol has drug interactions, but you may not know the extent and seriousness that some of these drug interactions can cause. Also, the way that the drug is broken down and excreted from the body (metabolism) is complicated and sometimes unpredictable, especially in children.
Review: Tramadol drug interactions
If you are known to be an “ultra-rapid metabolizer” you should not use tramadol. This means that you create the active M1 metabolite from tramadol more quickly than others, and are at risk for dangerous or even fatal respiratory depression or overdose.
Tramadol is known to interact with drugs that are affected by cytochrome P450 (CYP450) enzymes. Specifically it can interact with drugs that affect the 3A4 and 2D6 enzymes, and interactions may occur when starting or stopping drugs. Increased blood levels of tramadol or the active metabolite M1 may occur and be dangerous or fatal. There are can be many of potential complex interactions so it’s important you ask your pharmacist or doctor to check for drug interactions when using tramadol or tramadol ER.
- Use of tramadol with these agents can decrease OR increase the metabolism (break down and excretion) of tramadol or M1 in your body, leading to abnormally high or low blood levels of the drug.
- When blood levels are too high, symptoms of opioid toxicity and worsened side effects can occur.
- When blood levels are too low, opioid withdrawal and lack of pain control can occur.
- Drugs like ketoconazole, erythromycin, rifampin, St. John’s Wort, or carbamazepine may alter the blood levels of tramadol, but there are many others.
Serious side effects including seizures and serotonin syndrome may also occur due to drug interactions. Examples of drug classes where this might occur include the serotonin reuptake inhibitors (SSRIs, SNRIs), TCAs and MAO inhibitors (like phenelzine or linezolid) — all types of antidepressants. In fact, tramadol should never be used with an MAOI inhibitor or within 14 days of taking an MAOI. Taking tramadol with drugs that already have a seizure risk may worsen that risk.
Patients receiving serotonergic drugs (for example, the migraine class called “triptans”) may also be at a higher risk for serotonin syndrome.
- Brand names of triptans include: Imitrex, Zomig, Maxalt, and others.
- However, serotonin syndrome and elevated seizure risk can occur with many other medications, too.
- A drug review by your pharmacist can predict if you may be at risk for these dangerous effects.
The use of tramadol with benzodiazepines (or any other sedative, hypnotic or tranquilizer), anti-anxiety medication, muscle relaxant, anesthetic, antipsychotic, alcohol or other narcotic medications (including illegal drugs) or alcohol can lead to extreme sedation, slowed or stopped breathing (respiratory depression), coma and death.
- Clinicians should reserve concomitant prescribing for patients who have no other treatment options. Limit dosages and durations to the minimum required; and follow patients for signs and symptoms of respiratory depression and sedation
- Tramadol should not be combined with any CNS depressant-type drug unless under the direction of your doctor. Do NOT drink alcohol or use abuse illicit drugs, street drugs or other opioids while taking tramadol.
- You should avoid driving, operating machinery or other activities that require mental alertness until:
- the effects of the drug are known
- you are tolerant to the effects of tramadol
- you are sure you can safely drive.
- If the drug continues to impair your physical or mental ability, do not drive or perform potentially hazardous activities.
Patients should always have a drug interaction review completed each time they start a new medication, or even stop a medication, and that includes prescription drugs, herbals, over-the-counter (OTC) medicines, and supplements like vitamins. Your pharmacist can advise you on possible tramadol drug interactions, so be sure to ask.
4. Tramadol can be habit-forming
Tramadol is structurally related to the opioids like codeine and morphine and can lead to psychological and physical dependence, addiction, abuse, and withdrawal. People with a history of a drug-seeking behavior may be at greater risk of addiction, but illicit actions to obtain the drug can occur in people without a prior addiction, as well.
Do not abruptly stop taking tramadol as withdrawal symptoms like nausea, diarrhea, anxiety, sweating, difficulty in sleep, shivering, pain, tremors, or rarely, hallucinations may occur. Rapid discontinuation of opioid analgesics has resulted in serious withdrawal symptoms, uncontrolled pain, and suicide.
Withdrawal symptoms may also occur if tramadol is used with drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist / antagonist analgesics (pentazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). The analgesic effect of tramadol may also be reduced. Avoid the use of tramadol with these drugs.
Consult with your doctor before discontinuing tramadol treatment; do NOT discontinue treatment on your own. Withdrawal symptoms may be relieved by re-initiation of opioid therapy followed by a slow, dose reduction combined with symptomatic support, as directed by your doctor.
Takes steps to secure your tramadol in a safe place at home to prevent theft, accidental overdose or death. Keep out of the reach of children.
Learn More: Prescription Drug Addiction: Top Facts for You & Your Family
5. What is an Opioid Analgesic REMS?
Some medications have an inherent risk that require a restricted program known as a Risk Evaluation and Mitigation Strategy (REMS) to ensure safe use. All opioid drugs like tramadol have an Opioid Analgesic REMS program in place as mandated by the FDA.
- A REMS is a medication safety program for certain medications with serious safety concerns or dangerous side effects to help ensure the benefits of the medication outweigh its risks. The FDA may require a REMS and they are developed by the drug manufacturer.
- There are typically many steps in a REMS, and can involve education and certification of healthcare providers, patients, pharmacies, and drug wholesalers.
- Creation of a Medication Guide that is updated with important patient information is part of the Opioid Analgesic REMS. The patient receives this each time they fill their opioid prescription and should review for changes.
6. Tramadol is available in both immediate-release and extended-release formulations.
Both the immediate-release and extended-release formulation of tramadol are available generically and can possibly save you hundreds of dollars on your prescription. Do not use more than one tramadol product at a time. Do not exceed the dose prescribed by your doctor.
- tramadol 50 mg regular-release tablets (brand name: Ultram); the 100 mg products (brand and generic) have been discontinued.
- tramadol extended-release (ER) capsules (brand name: ConZip) come in strengths of 100 mg, 150 mg, 200 mg, and 300 mg.
- tramadol extended-release tablets comes in strengths of 100, 200, and 300 mg (brand name product no longer available).
If you prefer generic medications due to cost-savings, ask your physician to only write for generic drugs whenever possible. If you cannot afford your medication, do not walk away from the pharmacy. Ask your doctor or pharmacist for a more affordable alternative.
Related: Top 10 Ways to Save Money on Your Medication Costs
The extended-release form of tramadol is for around-the-clock treatment of pain and not for use on an as-needed basis. Tramadol extended-release tablets / capsules must be swallowed whole and intact; do not split, break, chew, crush or dissolve the product.
A combination product of tramadol and acetaminophen (Ultracet) is also available in both brand and generic form as a tablet.
- Combining tramadol with acetaminophen (Tylenol) may further help with pain and allow lower doses of tramadol to be used.
- However, Ultracet is not approved for use for more than 5 days.
- Also, be careful not to combine Ultracet with extra acetaminophen (Tylenol), as too much acetaminophen is toxic for your liver.
Learn more about generic drugs: Facts About Generic Drugs.
7. Special populations: the elderly, kidney or liver disease, and pregnancy.
Here’s another good reason not to share your tramadol with others: the dose you are prescribed may not be the right dose for someone else, and could lead to serious consequences like slowed or stopped breathing, coma, or even death.
Review tramadol dosing here.
As with many medications, if you are young, elderly, or have kidney or liver disease dose adjustments are often required.
- The dosing interval (how often you take the drug) may need to be adjusted, the actual dose of the drug may need to be reduced, and you may have a maximum daily dose you should not exceed.
- Talk to your doctor about the need for adjusted doses with any medication, including tramadol.
- Do not exceed the prescribed tramadol dose or dosing interval prescribed by your doctor.
Overdose: Naloxone (Narcan) will reverse some, but not all, symptoms caused by overdosage with tramadol, and the risk of seizures is also increased with naloxone administration. Monitor the patient until spontaneous respiration (breathing) is reliably reestablished. Extended-release tramadol will continue to release into the blood for 24 to 48 hours or longer following ingestion, meaning a prolonged period of monitoring may be needed.
Patients older than 65 years of age
- Doses should usually start at the low end of the dosing range and can be titrated upwards slowly based on tolerance and effectiveness.
Patients older than 75 years of age
- Maximum dose of regular-release tramadol oral tablets: 300 mg per day (in divided doses).
Pregnancy + Breastfeeding
Tell your doctor if you are pregnant or plan to become pregnant. If you use tramadol while you are pregnant, your baby could become dependent on the drug (addicted). Possibly fatal withdrawal symptoms may occur in your baby after it is born, causing death. Babies born dependent on habit-forming medicine may need medical treatment for several weeks.
Do not breastfeed while taking tramadol. This medicine can pass into your breast milk and cause drowsiness, breathing problems, or death in a nursing baby.
Learn More: Tramadol Pregnancy and Breastfeeding Warnings
Kidney Disease and Liver Disease
Over 30% of tramadol is excreted by the kidneys as the unchanged molecule, which means it could lead to toxic blood levels in patients with kidney disease.
- Tramadol is metabolized through the liver, so a patient with kidney or liver disease may require a change in dose, different dose interval, or maximum amount of drug taken each day.
- Some patients with severe kidney or liver impairment may not be candidates for tramadol treatment at all.
- Providers should consider monitoring renal function (such as creatinine clearance) with tramadol treatment, especially in the elderly, because this drug is substantially excreted by the kidney.
8. There are ways to engage with other patients using tramadol.
Your doctor should always be your first and final contact for advice on tramadol use. However, support groups may be helpful for patients who take tramadol, who use medications for pain relief, or who are in need of addiction support.
Joining one or more support groups is a great way to discover others taking related medications with similar medical conditions, keep up with the medical news, and share your own experience.
- Tramadol Support Group
- Ultram Support Group
- Fibromylagia Support Group
- Pain Support Group
- Addiction Support Group
- Opiate Dependence
- Depression Support Group
There are over 1300 reviews for tramadol from patients like you who use this drug for general pain, back pain, fibromyalgia and other various conditions (some of which may be off-label use, meaning the drug is not approved by the FDA for that particular use).
This information is NOT a complete overview of tramadol. It is NOT intended to endorse tramadol or recommend therapy. While these reviews may or may not be helpful to you, they are NOT a substitute for the expertise, skill, knowledge and judgement of your individual healthcare provider.
Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.
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Tramadol vs. Oxycodone: Comparison of Side Effects and Effectiveness
Oxycodone is a strong, semi-synthetic opioid that is closely regulated by the DEA because of the risk of addiction and abuse. Much like tramadol, oxycodone works on the user’s central nervous system, altering how they perceive pain. Unlike tramadol, oxycodone doesn’t have the impact of norepinephrine and serotonin reuptake inhibition, so it doesn’t have the mood-enhancing element of tramadol unless someone takes large doses and achieves a euphoric high.
Oxycodone functions as a pure opioid agonist, and it has a more rapid onset time than tramadol. For example, when comparing tramadol vs. oxycodone, you’ll see that oxycodone will usually start working with 20 to 30 minutes after taking it, with peak effects occurring in around one hour. The half-life of oxycodone is 3.5 to 4 hours, and the half-life of tramadol is 6.3 hours.
These numbers are important because they highlight some of the reasons there is a lower risk of abuse with tramadol vs. oxycodone. Usually, the more fast-acting an opioid is, the more likely it is to be abused. Of course, tramadol can be abused and can become addictive, but the risk is lower. In general, oxycodone is considered to have a high risk of physical and psychological dependence, while tramadol is considered to have a low risk. That’s why oxycodone is schedule II, and tramadol is schedule IV.
To further compare tramadol vs. oxycodone:
- Regarding effectiveness as a painkiller, oxycodone is usually more potent, and oxycodone has more rapid onset of pain relieving effects
- Tramadol does have a higher risk of seizures than oxycodone, particularly in people who already have a history of seizures.
- Oxycodone has a higher potential for abuse and addiction than tramadol.
Something else important to recognize when comparing tramadol vs. oxycodone is that tramadol isn’t associated with significant depression of the respiratory system. One of the most dangerous aspects of opioids like oxycodone is that they can cause significant and sometimes deadly respiratory depression, but tramadol doesn’t have a high risk of that occurring.
Also different when comparing tramadol vs. oxycodone is the potential interactions they have with other drugs. For example, with oxycodone people shouldn’t combine it with other central nervous depressants because it will further depress respiration. With tramadol, it’s important to avoid serotonin-based medicines because of the risk of serotonin syndrome.
To sum up the comparison of tramadol vs. oxycodone: oxycodone is stronger at relieving pain, but also more likely to lead to addiction and dependence. Tramadol has mood-boosting properties, but a lower risk of respiratory depression and tramadol also carries the risk of seizure.
Mechanism Of Action
ULTRAM® is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to μ-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin.
Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to μ-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in μ-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound (see Pharmacokinetics).
Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of ULTRAM®. Analgesia in humans begins approximately within one hour after administration and reaches a peak in approximately two to three hours.
Apart from analgesia, ULTRAM® administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, ULTRAM® has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed.
The analgesic activity of ULTRAM® is due to both parent drug and the M1 metabolite (see Mechanism of Action). Tramadol is administered as a racemate and both the and forms of both tramadol and M1 are detected in the circulation. Tramadol is well absorbed orally with an absolute bioavailability of 75%. Tramadol has a volume of distribution of approximately 2.7 L/kg and is only 20% bound to plasma proteins. Tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. One metabolite, M1, is pharmacologically active in animal models. The formation of M1 is dependent upon CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see DRUG INTERACTIONS). Tramadol and its metabolites are excreted primarily in the urine with observed plasma half-lives of 6.3 and 7.4 hours for tramadol and M1, respectively. Linear pharmacokinetics have been observed following multiple doses of 50 and 100 mg to steady-state.
Racemic tramadol is rapidly and almost completely absorbed after oral administration. The mean absolute bioavailability of a 100 mg oral dose is approximately 75%. The mean peak plasma concentration of racemic tramadol and M1 occurs at two and three hours, respectively, after administration in healthy adults. In general, both enantiomers of tramadol and M1 follow a parallel time course in the body following single and multiple doses although small differences (~ 10%) exist in the absolute amount of each enantiomer present.
Steady-state plasma concentrations of both tramadol and M1 are achieved within two days with q.i.d. dosing. There is no evidence of self-induction (see Figure 1.1 and Table 1.4 below).
Figure 1.1: Mean Tramadol and M1 Plasma Concentration Profiles after a Single 100 mg Oral Dose and after Twenty-Nine 100 mg Oral Doses of Tramadol HCl Given q.i.d.
Table 1.4: Mean (%CV) Pharmacokinetic Parameters for Racemic Tramadol and M1 Metabolite
The volume of distribution of tramadol was 2.6 and 2.9 L/kg in male and female subjects, respectively, following a 100 mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10 μg/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range.
Following oral administration, tramadol is extensively metabolized by a number of pathways, including CYP2D6 and CYP3A4, as well as by conjugation of parent and metabolites. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The major metabolic pathways appear to be N- and O- demethylation and glucuronidation or sulfation in the liver. Metabolite M1 (O-desmethyltramadol) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response (see DRUG INTERACTIONS).
Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P450. These individuals are “poor metabolizers” of debrisoquine, dextromethorphan, and tricyclic antidepressants, among other drugs. Based on a population PK analysis of Phase I studies in healthy subjects, concentrations of tramadol were approximately 20% higher in “poor metabolizers” versus “extensive metabolizers”, while M1 concentrations were 40% lower. In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 such as fluoxetine and its metabolite norfluoxetine, amitriptyline and quinidine inhibit the metabolism of tramadol to various degrees. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Concomitant use of serotonin reuptake inhibitors and MAO inhibitors may enhance the risk of adverse events, including seizure (see WARNINGS AND PRECAUTIONS) and serotonin syndrome.
Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 are 6.3 ± 1.4 and 7.4 ± 1.4 hours, respectively. The plasma elimination half-life of racemic tramadol increased from approximately six hours to seven hours upon multiple dosing.
Special Populations and Conditions
Pharmacokinetics of ULTRAM® tablets have not been studied in pediatric patients below 18 years of age.
Healthy elderly subjects aged 65 to 75 years have plasma tramadol concentrations and elimination half-lives comparable to those observed in healthy subjects less than 65 years of age. In subjects over 75 years, maximum serum concentrations are elevated (208 vs. 162 ng/mL) and the elimination half-life is prolonged (7 vs. 6 hours) compared to subjects 65 to 75 years of age. Adjustment of the daily dose is recommended for patients older than 75 years (see DOSAGE AND ADMINISTRATION).
The absolute bioavailability of tramadol was 73% in males and 79% in females. The plasma clearance was 6.4 mL/min/kg in males and 5.7 mL/min/kg in females following a 100 mg i.v. dose of tramadol. Following a single oral dose, and after adjusting for body weight, females had a 12% higher peak tramadol concentration and a 35% higher area under the concentration-time curve compared to males. The clinical significance of this difference is unknown.
Metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver, resulting in both a larger area under the concentration time curve for tramadol and longer tramadol and M1 elimination half-lives (13 hrs for tramadol and 19 hrs for M1). In cirrhotic patients, adjustment of the dosing regimen is recommended (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Excretion of tramadol and metabolite M1 is reduced in patients with creatinine clearance of less than 30 mL/min, adjustment of dosing regimen in this patient population is recommended. The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).
ULTRAM® was evaluated in single-dose trials (dental and surgery), multiple-dose, . Clinical trials in non-malignant pain included patients with osteoarthritis, low back pain, diabetic neuropathy and fibromyalgia. These trials included a randomized, double-blind, parallel group design, and in each of the single-dose and short-term multiple-dose trials tramadol was compared to a standard reference analgesic (either codeine, ASA/codeine or APAP/propoxyphene), placebo or to both. The active controls were included to establish model sensitivity. The efficacy of tramadol in these trials was established based on Total Pain Relief (TOTPAR), Sum of Pain Intensity Difference (SPID) and time to remedication.
Collectively, a total of 2549 patients with dental pain, 1940 patients with surgical pain, 170 patients with chronic malignant pain, 119 patients with sub-acute low back pain, and 2046 patients with chronic non-malignant pain were enrolled into the 28 efficacy trials. Of the 6824 total patients enrolled into these trials, 4075 were randomized to a tramadol treatment arm.
Acute Pain, Single- and Multiple-Dose Studies
ULTRAM® has been given in single oral doses of 50, 75 and 100 mg to patients with pain following surgical procedures and pain following oral surgery (extraction of impacted molars).
Results of these trials demonstrated statistically superior pain relief for tramadol compared to placebo. Data from these key trials provide information regarding the optimal analgesic dosage range of tramadol.
In single-dose dental trials, tramadol was superior to placebo at doses of 100 mg or greater (p ≤ 0.05). In addition, tramadol at doses of 100mg or greater were equivalent to or statistically superior to the reference analgesics for Total Pain Relief (TOTPAR) and Sum of Pain Intensity Difference (SPID) across the entire evaluation interval. The results of the multiple-dose short-term trials in acute pain also provide evidence for efficacy of tramadol in the management of acute pain.
Tramadol has been studied in three long-term controlled trials involving a total of 820 patients, with 530 patients receiving tramadol. Patients with a variety of chronic painful conditions were studied in double-blind trials of one to three months duration.
Two titration trials, TPS DOS and CAPSS-047, provide information regarding appropriate dose titration during chronic use of tramadol. These trials show that a longer titration period can significantly reduce the incidence of adverse events, and the frequency of withdrawal due to adverse events, leading to improved tolerability and overall benefit-risk profile. Efficacy evaluations in these studies suggest that slowing the rate of titration improves tolerability and does not negatively impact on drug efficacy.
In a randomized, blinded clinical study with 129 to 132 patients per group, a 10-day titration to a daily ULTRAM® dose of 200 mg (50 mg q.i.d.), attained in 50 mg increments every 3 days, was found to result in fewer discontinuations due to dizziness or vertigo than titration over only 4 days or no titration. In a second study with 54 to 59 patients per group, patients who had nausea or vomiting when titrated over 4 days were randomized to re-initiate ULTRAM® therapy using slower titration rates.
A 16-day titration schedule, starting with 25 mg qAM and using additional doses in 25 mg increments every third day to 100 mg/day (25 mg q.i.d.), followed by 50 mg increments in the total daily dose every third day to 200 mg/day (50 mg q.i.d.), resulted in fewer discontinuations due to any cause than did a 10-day titration schedule. See Figure 2.1.
Figure 2.1: Protocol CAPSS-047 – Time to Discontinuation Due to Nausea/Vomiting
Tramadol HCl, 2–1-(3-methoxyphenyl) cyclohexanol HCl, is a centrally acting synthetic analgesic compound. It is thought to produce its analgesic effect through at least two complementary mechanisms of action: agonist activity at the μ-opioid receptor and weak inhibition of neuronal monoamine reuptake. These dual activities are observed in studies conducted in vitro as well as in nonclinical animal models of antinociception. In studies conducted in vitro, tramadol inhibited binding to native rat μ-opioid receptor at approximately the same concentration at which it blocked the reuptake of norepinephrine and serotonin. The K1 values for μ-opioid receptor affinity and monoamine reuptake inhibitory activities are 2.1 and ~ 1 μM, respectively. Tramadol affinities for recombinant human opioid receptors (K1 = 17 μM) were slightly weaker than those observed at the rat receptors. Apart from analgesia, tramadol may produce a constellation of symptoms similar to that of an opioid.
Tramadol is an efficacious analgesic in a wide variety of standard analgesic models of acute, tonic, chronic, or neuropathic pain. In some of these studies, specific antagonists were used to probe the mechanism of tramadol’s antinociceptive action. In contrast to the full blockade of morphine antinociception by naloxone, the antinociceptive action of tramadol in most tests is only partially blocked by naloxone. Furthermore, although the antinociception of morphine is unaffected by the alpha2-adrenergic antagonist yohimbine or the serotonergic antagonist ritanserin, each of these antagonists reduces tramadol’s antinociception. These pharmacologic studies suggest the contribution of both opioid and monoamine mechanisms to tramadol antinociception.
In drug interaction studies carried out with tramadol, a substantial increase in toxicity was found after pretreatment with an MAO inhibitor, tranylcypromine. The antinociceptive effect of the compound was reduced by concomitant administration of barbiturates and atropine, and was virtually eliminated by tranylcypromine. Physostigmine potentiated the antinociceptive effect of a sub-maximal dose of tramadol. Other potential drug interactions based on enzyme induction or displacement from protein binding were thought to be unlikely with tramadol as no inductive effect on liver enzymes has been found for this agent and the protein binding is too low to induce relevant interference with the binding of other compounds.
Tramadol was rapidly absorbed after oral administration in the mouse, rat, and dog. In dogs, the mean absolute bioavailability of a single 20 mg/kg oral dose of tramadol (Avicel formulation in gelatin capsules) was 81.8%, with maximum plasma concentrations achieved in about one hour. Distribution of radioactivity into tissues was rapid following the intravenous administration of 14C-labelled tramadol to rats, with the highest concentration of radioactivity found in the liver. Radioactivity levels in the brain were comparable to plasma levels for the first 2 hours post-injection, demonstrating that the drug crosses the blood brain barrier. Concentrations in the kidneys, lungs, spleen, and pancreas were also higher than the serum concentration.
The major metabolic pathway was qualitatively similar for all species studied, including mouse, rat, hamster, guinea pig, rabbit, and man, and involved both Phase I (N- and O-demethylation and 4-hydroxylation; eight metabolites) and Phase II (glucuronidation or sulfation; thirteen metabolites) reactions. The primary metabolite mono-O-desmethyltramadol (M1) has antinociceptive activity. In biochemical studies, (±) mono-O-desmethyltramadol and its enantiomers each had greater affinity for opioid receptors and were less potent inhibitors of monoamine uptake than were the corresponding parent compounds.
Excretion was primarily by the renal route in the animal species studied. After oral administration, fecal excretion was approximately 13% in rats and dogs, and 80% of 14C-labelled tramadol doses were excreted in the urine within 72 to 216 hours of dosing. Amounts of unchanged tramadol excreted in the urine were higher in man (approximately 30% of the dose) than in animals (approximately 1%).
Tramadol is a mild inducer of ethoxycoumarin deethylase activity in the mouse and dog.
The acute toxicity of tramadol hydrochloride has been examined in the rat. The results of the study are summarized in the following table.
Table 2.1: Acute Toxicity Studies Summary
Multi-dose toxicity studies were conducted in rats and dogs. The following table summarizes the results of the two pivotal multi-dose studies.
Table 2.2: Multi-dose Toxicity Studies–Protocol Summaries/Results
|Species/Strain Age/B.W.||No./Group/ Duration/Route||Dosage (mg/kg/day)||Evaluated Parameters||Results|
|Rat Crl:CD® BR, VAF/Plus®||10/3 mo/p.o. (gavage)||1) Vehicle Control: 0.5% Methocel (10 mL/kg/day)||Mortality, clinical observations, B.W., food consumption, ophthalmological examination, drug metabolism, hematology, coagulation, clinical chemistry, urinalysis, organ weights, gross pathology, histopathology|| Vehicle Control: Four M deaths (attributed to dosing errors); alopecia in both sexes
7.5/65: Alopecia in both sexes; liver weights in males
22.5/195: One M death (cause of death not determined); alopecia in both sexes; liver weights in males; slightly urine volume in females
|45/390: Alopecia, salivation, slightly higher urine volume in both sexes; mild treatment related increases in K+ concentration, slightly ↓ RBC, MCV, MCH, liver weights, slightly ↓ ALT and AST activity and ALP in females|
|3) Tramadol: 45|
|4) APAP: 390||45: Alopecia, salivation, in both sexes; slightly ↓ ALT and AST activity and ALP in females.|
|390: salivation, slightly higher urine volume in both sexes; liver weights in males; slightly ↓ RBC, MCV, MCH in males; alopecia, mild treatment related increases in K+ concentration, slightly ↓ ALT and AST activity and ALP in females.Additional findings: (1) higher kidney weights in males dosed with APAP or tramadol/APAP; (2) lower adrenal gland weights in males dosed with tramadol and/or APAP.|
|ALP = alkaline phosphatase; ALT = alanine aminotransferase; APAP = acetaminophen; AST = aspartate aminotransferase; K = potassium; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; mo = month; p.o. = oral; RBC = red blood cell; wk = week; = increased; ↓ = decreased|
Table 2.2: Multi-dose Toxicity Studies – Protocol Summaries/Results (continued)
A slight, but statistically significant, increase in two common murine tumors, pulmonary and hepatic, was observed in a mouse carcinogenicity study, particularly in aged mice. Mice were dosed orally up to 30 mg/kg (90 mg/m² or 0.36 times the maximum daily human dosage of 246 mg/m²) for approximately two years, although the study was not done with the Maximum Tolerated Dose. This finding is not believed to suggest risk in humans. No such finding occurred in a rat carcinogenicity study (dosing orally up to 30 mg/kg, 180 mg/m², or 0.73 times the maximum daily human dosage).
Tramadol was not mutagenic in the following assays: Ames Salmonella microsomal activation test, CHO/HPRT mammalian cell assay, mouse lymphoma assay (in the absence of metabolic activation), dominant lethal mutation tests in mice, chromosome aberration test in Chinese hamsters, and bone marrow micronucleus tests in mice and Chinese hamsters. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats. Overall, the weight of evidence from these tests indicates that tramadol does not pose a genotoxic risk to humans.
No effects on fertility were observed for tramadol at oral dose levels up to 50 mg/kg (300 mg/m²) in male rats and 75 mg/kg (450 mg/m²) in female rats. These dosages are 1.2 and 1.8 times the maximum daily human dosage of 246 mg/m², respectively.
Tramadol has been shown to be embryotoxic and fetotoxic in mice, (120 mg/kg or 360 mg/m²), rats ( ≥ 25 mg/kg or 150 mg/m²) and rabbits ( ≥ 75 mg/kg or 900 mg/m²) at maternally toxic dosages, but was not teratogenic at these dose levels. These dosages on a mg/m² basis are 1.4, ≥ 0.6, and ≥ 3.6 times the maximum daily human dosage (246 mg/m²) for mouse, rat and rabbit, respectively.
No drug-related teratogenic effects were observed in progeny of mice (up to 140 mg/kg or 420 mg/m²), rats (up to 80 mg/kg or 480 mg/m²) or rabbits (up to 300 mg/kg or 3600 mg/m²) treated with tramadol by various routes. Embryo and fetal toxicity consisted primarily of decreased fetal weights, skeletal ossification and increased supernumerary ribs at maternally toxic dose levels. Transient delays in developmental or behavioral parameters were also seen in pups from rat dams allowed to deliver. Embryo and fetal lethality were reported only in one rabbit study at 300 mg/kg (3600 mg/m²), a dose that would cause extreme maternal toxicity in the rabbit. The dosages listed for mouse, rat and rabbit are 1.7, 1.9 and 14.6 times the maximum daily human dosage (246 mg/m²), respectively.
Tramadol was evaluated in peri- and post-natal studies in rats. Progeny of dams receiving oral (gavage) dose levels of 50 mg/kg (300 mg/m² or 1.2 times the maximum daily human tramadol dosage) or greater had decreased weights, and pup survival was decreased early in lactation at 80 mg/kg (480 mg/m² or 1.9 and higher the maximum daily human dose).
Table 2.3: Reproductive Study – Summary
The physical dependence liability potential associated with the chronic use of tramadol has been evaluated in a number of animal studies, including investigations in the mouse, rat, and monkey. A slight degree of antinociceptive tolerance to tramadol evolved in the mouse studies, but there was little or no indication of the development of physical dependence. No evidence of dependence was observed in the rat study. However, in dogs addicted to morphine, withdrawal symptoms were relieved by tramadol. In primate studies, which evaluated the physical dependence and reinforcement properties of tramadol, the physical dependence of the drug was deemed to be low.
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