Side Effects of Ultracet (tramadol and acetaminophen)

Ultracet (tramadol and acetaminophen) is a combination of analgesics used to relieve moderate, acute pain such as pain following dental or surgical procedures. 

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:

• constipation,
• tiredness, and
• increased sweating. 

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:

• anxiety,
• sweating,
• insomnia,
• chills,
• pain,
• nausea,
• diarrhea,
• tremors, and
• hallucinations.

Drug interactions of Ultracet include carbamazepine or rifampin, which can make the tramadol less effective. 

The following may reduce elimination of tramadol, increasing the risk for serious side effects from tramadolquinidine: 

• fluoxetine,
• paroxetine,
• amitriptyline,
• ketoconazole, or
• erythromycin. 

Combining tramadol with the following may result in severe side effects such as seizures or a condition called serotonin syndrome:

• monoamine oxidase inhibitors (MAOIs),
• selective serotonin inhibitors (SSRIs),
• St. John's wort, or
• triptans. 

Tramadol may increase central nervous system and respiratory depression when combined with alcohol, anesthetics, narcotics, tranquilizers, or sedative hypnotics. 

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. 

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:

• anxiety,
• sweating,
• insomnia,
• rigors,
• pain,
• nausea,
• diarrhea,
• tremors,
• and hallucinations.

An overdose of acetaminophen can result in severe liver damage.

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
• Hepatotoxicity
• Interactions with Benzodiazepines and Other CNS Depressants
• Serotonin Syndrome
• Seizures
• Suicide
• Adrenal Insufficiency
• Severe Hypotension
• Gastrointestinal Adverse Reactions
• Hypersensitivity Reactions
• Withdrawal

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:

• constipation,
• diarrhea,
• nausea,
• somnolence,
• anorexia,
• dizziness, and
• sweating increased.

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%)

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

Central and Peripheral Nervous System - Dizziness, headache, tremor

Gastrointestinal System - Abdominal pain, constipation, diarrhea, dyspepsia, flatulence, dry mouth, nausea, vomiting

Psychiatric Disorders - Anorexia, anxiety, confusion, euphoria, insomnia, nervousness, somnolence

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.

Body as a Whole - Chest pain, rigors, syncope, withdrawal syndrome

Cardiovascular Disorders - Hypertension, aggravated hypertension, hypotension

Central and Peripheral Nervous System - Ataxia, convulsions, hypertonia, migraine, aggravated migraine, involuntary muscle contractions, paresthesias, stupor, vertigo

Gastrointestinal System - Dysphagia, melena, tongue edema

Hearing and Vestibular Disorders - Tinnitus

Heart Rate and Rhythm Disorders - Arrhythmia, palpitation, tachycardia

Liver and Biliary System - Hepatic function abnormal

Metabolic and Nutritional Disorders - Weight decrease

Psychiatric Disorders - Amnesia, depersonalization, depression, drug abuse, emotional lability, hallucination, impotence, paroniria, abnormal thinking

Red Blood Cell Disorders - Anemia

Respiratory System - Dyspnea

Urinary System - Albuminuria, micturition disorder, oliguria, urinary retention

Vision Disorders - Abnormal vision

Postmarketing Experience

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:

• vasodilation,
• orthostatic hypotension,
• myocardial ischemia,
• pulmonary edema,
• allergic reactions (including anaphylaxis and urticaria, Stevens-Johnson syndrome/TENS),
• cognitive dysfunction,
• difficulty concentrating,
• depression,
• suicidal tendency,
• hepatitis,
• 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.

Table 2 includes clinically significant interactions with Ultracet.

Table 2: Clinically Significant Drug Interactions with Ultracet

Controlled Substance

Ultracet contains tramadol, a Schedule IV controlled substance.

Abuse

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.

Parenteral drug abuse is commonly associated with transmission of infectious diseases such as hepatitis and HIV.

Dependence

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:

• restlessness,
• lacrimation,
• rhinorrhea,
• yawning,
• perspiration,
• chills,
• myalgia, and
• mydriasis.

Other signs and symptoms also may develop, including:

• irritability,
• anxiety,
• backache,
• joint pain,
• weakness,
• abdominal cramps,
• insomnia,
• nausea,
• anorexia,
• vomiting,
• 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.