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- Does Ultracet (tramadol and acetaminophen) cause side effects?
- What are the important side effects of Ultracet (tramadol and acetaminophen)?
- Ultracet (tramadol and acetaminophen) side effects list for healthcare professionals
- What drugs interact with Ultracet (tramadol and acetaminophen)?
- Does Ultracet (tramadol and acetaminophen) cause addiction or withdrawal symptoms?
Does Ultracet (tramadol and acetaminophen) cause side effects?
Tramadol binds to the opioid receptor on nerves (the same mechanism that is responsible for the effectiveness of narcotics, such as morphine), and it also inhibits the reuptake by nerves of two neurotransmitters, serotonin and norepinephrine, that the nerves use to communicate with one another.
This inhibition may lead to reduced transmission of pain signals from nerve to nerve in the spinal cord and brain. Acetaminophen achieves pain relief in the spinal cord and brain by increasing the threshold to pain. It does this by inhibiting an enzyme that makes prostaglandins.
Common side effects of Ultracet include:
Serious side effects of Ultracet include:
- severe liver damage (due to overdose of acetaminophen).
Because tramadol is chemically related to the narcotic class of drugs, it can cause psychological or physical dependence.
Seizures have been reported.
Abrupt withdrawal of tramadol may result in side effects including:
The following may reduce elimination of tramadol, increasing the risk for serious side effects from tramadolquinidine:
- monoamine oxidase inhibitors (MAOIs),
- selective serotonin inhibitors (SSRIs),
- St. John's wort, or
What are the important side effects of Ultracet (tramadol and acetaminophen)?
Ultracet usually is well-tolerated. The most common side effects are:
- constipation (1 in 17 patients),
- tiredness (1 in 17), and
- increased sweating (1 in 25).
Because tramadol is chemically related to the narcotic class of drugs such as morphine and hydrocodone (Vicodin ES, Anexsia, Lorcet, Lorcet Plus, Norco), it can cause psychological or physical dependence. Some patients who received tramadol have reported seizures.
Abrupt withdrawal of tramadol may result in the following side effects:
An overdose of acetaminophen can result in severe liver damage.
Ultracet (tramadol and acetaminophen) side effects list for healthcare professionals
The following serious adverse reactions are discussed, or described in greater detail, in other sections:
- Addiction, Abuse, and Misuse
- Life-Threatening Respiratory Depression
- Neonatal Opioid Withdrawal Syndrome
- Interactions with Benzodiazepines and Other CNS Depressants
- Serotonin Syndrome
- Adrenal Insufficiency
- Severe Hypotension
- Gastrointestinal Adverse Reactions
- Hypersensitivity Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The most common incidence of treatment-emergent adverse events ( ≥ 3.0%) in subjects from clinical trials was:
Table 1 shows the incidence rate of treatment-emergent adverse events reported in ≥ 2.0% of subjects over five days of Ultracet use in clinical trials (subjects took an average of at least 6 tablets per day).
Table 1: Incidence of Treatment-Emergent Adverse Events ( ≥ 2.0%)
|Gastrointestinal System Disorders|
|Central & Peripheral Nervous System|
|Skin and Appendages|
|Reproductive Disorders, Male*|
|*Number of males = 62|
Incidence at least 1%, causal relationship at least possible or greater:
The following lists adverse reactions that occurred with an incidence of at least 1% in single-dose or repeated-dose clinical trials of Ultracet.
Body as a Whole - Asthenia, fatigue, hot flushes
Skin and Appendages - Pruritus, rash, increased sweating
Selected Adverse events occurring at less than 1%:
The following lists clinically relevant adverse reactions that occurred with an incidence of less than 1% in Ultracet clinical trials.
Liver and Biliary System - Hepatic function abnormal
Metabolic and Nutritional Disorders - Weight decrease
Red Blood Cell Disorders - Anemia
Respiratory System - Dyspnea
Vision Disorders - Abnormal vision
The following adverse reactions have been identified during post approval use of tramadol-containing products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Serotonin syndrome: Cases of serotonin syndrome, a potentially life-threatening condition, have been reported during concomitant use of opioids with serotonergic drugs.
Adrenal insufficiency: Cases of adrenal insufficiency have been reported with opioid use, more often following greater than one month of use.
Anaphylaxis: Anaphylaxis has been reported with ingredients contained in Ultracet.
Androgen deficiency: Cases of androgen deficiency have occurred with chronic use of opioids.
Eye disorders - miosis, mydriasis
Metabolism and nutrition disorders - Cases of hypoglycemia have been reported very rarely in patients taking tramadol. Most reports were in patients with predisposing risk factors, including diabetes or renal insufficiency, or in elderly patients.
Nervous system disorders - movement disorder, speech disorder
Psychiatric disorders - delirium
Other clinically significant adverse experiences previously reported with tramadol hydrochloride:
Other events which have been reported with the use of tramadol products and for which a causal association has not been determined include:
- orthostatic hypotension,
- myocardial ischemia,
- pulmonary edema,
- allergic reactions (including anaphylaxis and urticaria, Stevens-Johnson syndrome/TENS),
- cognitive dysfunction,
- difficulty concentrating,
- suicidal tendency,
- liver failure, and
- gastrointestinal bleeding.
Reported laboratory abnormalities included elevated creatinine and liver function tests. Serotonin syndrome (whose symptoms may include mental status change, hyperreflexia, fever, shivering, tremor, agitation, diaphoresis, seizures, and coma) has been reported with tramadol when used concomitantly with other serotonergic agents such as SSRIs and MAOIs.
What drugs interact with Ultracet (tramadol and acetaminophen)?
Table 2 includes clinically significant interactions with Ultracet.
Table 2: Clinically Significant Drug Interactions with
|Inhibitors of CYP2D6|
|Clinical Impact:||The concomitant use of Ultracet and CYP2D6 inhibitors may result in an increase in the plasma concentration of tramadol and a decrease in the plasma concentration of M1, particularly when an inhibitor is added after a stable dose of Ultracet is achieved. Since M1 is a more potent p-opioid agonist, decreased M1 exposure could result in decreased therapeutic effects, and may result in signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol. Increased tramadol exposure can result in increased or prolonged therapeutic effects and increased risk for serious adverse events including seizures and serotonin syndrome. After stopping a CYP2D6 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease and the M1 plasma concentration will increase which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, and may cause potentially fatal respiratory depression.|
|Intervention:||If concomitant use of a CYP2D6 inhibitor is necessary, follow patients closely for adverse reactions including opioid withdrawal, seizures and serotonin syndrome. If a CYP2D6 inhibitor is discontinued, consider lowering Ultracet dosage until stable drug effects are achieved. Follow patients closely for adverse events including respiratory depression and sedation.|
|Examples||Quinidine, fluoxetine, paroxetine and bupropion|
|Inhibitors of CYP3A4|
|Clinical Impact:||The concomitant use of Ultracet and CYP3A4 inhibitors can increase the plasma concentration of tramadol and may result in a greater amount of metabolism via CYP2D6 and greater levels of M1. Follow patients closely for increased risk of serious adverse events including seizures and serotonin syndrome, and adverse reactions related to opioid toxicity including potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Ultracet is achieved.
After stopping a CYP3A4 inhibitor, as the effects of the inhibitor decline, the tramadol plasma concentration will decrease, resulting in decreased opioid efficacy and possibly signs and symptoms of opioid withdrawal in patients who had developed physical dependence to tramadol.
|Intervention:||If concomitant use is necessary, consider dosage reduction of Ultracet until stable drug effects are achieved. Follow patients closely for seizures and serotonin syndrome, and signs of respiratory depression and sedation at frequent intervals.
If a CYP3A4 inhibitor is discontinued, consider increasing the Ultracet dosage until stable drug effects are achieved and follow patients for signs and symptoms of opioid withdrawal.
|Examples||Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g. ketoconazole), protease inhibitors (e.g., ritonavir)|
|Clinical Impact:||The concomitant use of Ultracet and CYP3A4 inducers can decrease the
plasma concentration of tramadol, resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol.
After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase, which could increase or prolong both the therapeutic effects and adverse reactions, and may cause serious respiratory depression, seizures and serotonin syndrome.
|Intervention:||If concomitant use is necessary, consider increasing the Ultracet dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Ultracet dosage reduction and monitor for seizures and serotonin syndrome, and signs of sedation and respiratory depression. Patients taking carbamazepine, a CYP3A4 inducer, may have a significantly reduced analgesic effect of tramadol. Because carbamazepine increases tramadol metabolism and because of the seizure risk associated with tramadol, concomitant administration of Ultracet and carbamazepine is not recommended.|
|Examples:||Rifampin, carbamazepine, phenytoin|
|Benzodiazepines and Other Central Nervous System (CNS) Depressants|
|Clinical Impact:||Due to additive pharmacologic effect, the concomitant use of benzodiazepines or other CNS depressants, including alcohol, can increase the risk of hypotension, respiratory depression, profound sedation, coma, and death.|
|Intervention:||Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients closely for signs of respiratory depression and sedation.|
|Examples:||Benzodiazepines and other sedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol.|
|Clinical Impact:||The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.|
|Intervention:||If concomitant use is warranted, carefully observe the patient, particularly during treatment initiation and dose adjustment. Discontinue Ultracet if serotonin syndrome is suspected.|
|Examples:||Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, 5-HT3 receptor antagonists, drugs that affect the serotonin neurotransmitter system (e.g., mirtazapine, trazodone, tramadol), monoamine oxidase (MAO) inhibitors (those intended to treat psychiatric disorders and also others, such as linezolid and intravenous methylene blue).|
|Monoamine Oxidase Inhibitors (MAOIs)|
|Clinical Impact:||MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).|
|Intervention:||Do not use Ultracet in patients taking MAOIs or within 14 days of stopping such treatment.|
|Examples:||phenelzine, tranylcypromine, linezolid|
|Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics|
|Clinical Impact:||May reduce the analgesic effect of Ultracet and/or precipitate withdrawal symptoms.|
|Intervention:||Avoid concomitant use.|
|Examples:||butorphanol, nalbuphine, pentazocine, buprenorphine|
|Clinical Impact:||Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.|
|Intervention:||Monitor patients for signs of respiratory depression that may be greater than otherwise expected and decrease the dosage of Ultracet and/or the muscle relaxant as necessary.|
|Clinical Impact:||Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone.|
|Intervention||Monitor patients for signs of diminished diuresis and/or effects on blood pressure and increase the dosage of the diuretic as needed|
|Clinical Impact:||The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.|
|Intervention:||Monitor patients for signs of urinary retention or reduced gastric motility when Ultracet is used concomitantly with anticholinergic drugs.|
|Clinical Impact:||Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity.|
|Intervention:||Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed.|
|Clinical Impact:||Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect, including elevation of prothrombin times.|
|Intervention:||Monitor the prothrombin time of patients on warfarin for signs of an interaction and adjust the dosage of warfarin as needed.|
Does Ultracet (tramadol and acetaminophen) cause addiction or withdrawal symptoms?
Ultracet contains tramadol, a Schedule IV controlled substance.
Ultracet contains tramadol, a substance with a high potential for abuse similar to other opioids and can be abused and is subject to misuse, addiction, and criminal diversion.
All patients treated with opioids require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.
Prescription drug abuse is the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.
Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and includes: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful, or potentially harmful, consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.
“Drug seeking” behavior is very common in persons with substance use disorders. Drug seeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated “loss” of prescriptions, tampering with prescriptions, and reluctance to provide prior medical records or contact information for other treating physician(s).
“Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers and people suffering from untreated addiction. Preoccupation with achieving adequate pain relief can be appropriate behavior in a patient with poor pain control.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Health care providers should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.
Ultracet, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by state and federal law, is strongly advised.
Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.
Risks Specific To Abuse Of Ultracet
Ultracet is for oral use only. Abuse of Ultracet poses a risk of overdose and death. The risk is increased with concurrent abuse of Ultracet with alcohol and other central nervous system depressants.
Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.
Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dosage reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity (e.g., naloxone, nalmefene), mixed agonist/antagonist analgesics (e.g., pentazocine, butorphanol, nalbuphine), or partial agonists (e.g., buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.
Ultracet should not be abruptly discontinued in a physically dependent patient. If Ultracet is abruptly discontinued in a physically-dependent patient, a withdrawal syndrome may occur. Some or all of the following can characterize this syndrome:
Other signs and symptoms also may develop, including:
- joint pain,
- abdominal cramps,
- diarrhea, or
- increased blood pressure, respiratory rate, or heart rate.
Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal signs.
Ultracet (tramadol and acetaminophen) is a combination of analgesics used to relieve moderate, acute pain such as pain following dental or surgical procedures. Common side effects of Ultracet include constipation, tiredness, and increased sweating. Safe use of Ultracet during pregnancy has not been established. There have been reports of neonatal seizures, neonatal withdrawal syndrome, fetal death, and stillbirth. Tramadol is excreted in breast milk. Safe use of Ultracet in nursing mothers has not been established. Consult your doctor before breastfeeding.
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Professional side effects, drug interactions, and addiction sections courtesy of the U.S. Food and Drug Administration.