Ultram (tramadol) Side Effects, Warnings, and Interactions

Ultram,Ultram ER, andConzip(tramadol) is apain reliever(analgesic) similar to morphine used to manage moderate to moderately severepain．Extended release tablets are used for moderate to moderately severechronic painin adults who require continuous treatment for an extended period. Common side effects ofUltram,Ultram ER, andConzipinclude

• nausea,
• constipation,
• dizziness,
• headache,
• euphoria,
• indigestion,
• spasticity,
• weakness,
• drowsiness, and
• vomiting．

Ultram, Ultram ER, and Conzip are not a nonsteroidal anti-inflammatorydrugs(NSAIDs), and do not have the increased risk of stomach ulcers andinternal bleedingthat can occur withNSAIDs．

Less commonly reported side effects of Ultram, Ultram ER, and Conzip include

• itching,
• sweating,
• dry mouth,
• diarrhea,
• rash,
• visual disturbances,
• spinning sensation (vertigo),
• seizures, and
• serotonin syndromewhen combined with otherdrugsthat also increase serotonin.

Withdrawal symptoms including restlessness, tearing, yawning,sweating,chills,muscle pain,anxiety, backache,joint pain,weakness, abdominalcramps,insomnia,nausea,weight loss,vomiting,diarrhea, and increased官网地址bwin, respiratory rate, andheartrate may occur if you suddenly stop taking Ultram, Ultram ER, and Conzip.

Drug interactions片剂,片剂呃,Conzip包括carbamazepine,,nidine,monoamine oxidase inhibitors(MAOIs), selective serotonin inhibitors (SSRIs),alcohol, anesthetics, narcotics, tranquilizers, and sedativehypnotics．The safety of, Ultram ER, and Conzip duringpregnancyhas not been established. Mothers who arebreastfeedingshould not take, Ultram ER, and Conzip because the infant may develop side effects, and will develop symptoms of withdrawal and difficultybreathing．

The following serious adverse reactions are described, or described in greater detail, in other sections:

• Addiction, Abuse, and Misuse
• Life-Threatening RespiratoryDepression
• Ultra-Rapid Metabolism ofTramadoland Other Risk Factors for Life-threatening RespiratoryDepression in Children
• NeonatalOpioid Withdrawal Syndrome
• Interactions withBenzodiazepinesor Other CNS Depressants
• Serotonin Syndrome
• Seizures
• Suicide
• Adrenal Insufficiency
• SevereHypotension
• Gastrointestinal Adverse Reactions
• Hypersensitivity Reactions
• Withdrawal

Clinical Trials Experience

Becauseclinical trialsare conducted under widely varying conditions, adverse reaction rates observed in theclinical trialsof a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Ultram was administered to 550 patients during the double-blind or open-label extension periods in U.S. studies of chronic nonmalignantpain．这些患者中,有375名65岁或老r. Table 1 reports the cumulative incidence rate of adverse reactions by 7, 30 and 90 days for the most frequent reactions (5% or more by 7 days). The most frequently reported events were in the central nervous system and gastrointestinal system. Although the reactions listed in the table are felt to be probably related to Ultram administration, the reported rates also include some events that may have been due to underlying disease or concomitant medication. The overall incidence rates of adverse experiences in these trials were similar for Ultram and the active control groups,TYLENOLwithCodeine#3 (acetaminophen300 mg withcodeinephosphate 30 mg), andaspirin325 mg withcodeinephosphate 30 mg, however, the rates of withdrawals due to adverse events appeared to be higher in the Ultram groups.

Table 1: Cumulative Incidence of Adverse Reactions for Ultram in Chronic Trials of NonmalignantPain(N=427)

	Up to 7 Days	Up to 30 Days	Up to 90 Days
Dizziness/Vertigo	26%	31%	33%
Nausea	24%	34%	40%
Constipation	24%	38%	46%
Headache	18%	26%	32%
Somnolence	16%	23%	25%
Vomiting	9%	13%	17%
Pruritus	8%	10%	11%
“CNS Stimulation”1	7%	11%	14%
Asthenia	6%	11%	12%
Sweating	6%	7%	9%
Dyspepsia	5%	9%	13%
Dry Mouth	5%	9%	10%
Diarrhea	5%	6%	10%
1“CNS Stimulation” is a composite of nervousness,anxiety, agitation,tremor, spasticity,euphoria, emotional lability andhallucinations

Incidence 1% To Less Than 5% Possibly Causally Related

The following lists adverse reactions that occurred with an incidence of 1% to less than 5% in clinical trials, and for which the possibility of a causal relationship with Ultram exists.

Body as a Whole:Malaise.

Cardiovascular:血管舒张。

Central Nervous System:Anxiety,Confusion, Coordination disturbance,Euphoria, Miosis, Nervousness,Sleepdisorder.

Gastrointestinal:Abdominal pain,Anorexia,Flatulence．

Musculoskeletal:Hypertonia.

Skin:Rash．

Special Senses:Visual disturbance.

Urogenital:Menopausal symptoms, Urinary frequency,Urinary retention．

Incidence Less Than 1%, possibly Causally Related

The following lists adverse reactions that occurred with an incidence of less than 1% in clinical trials of tramadol and/or reported in post-marketing experience with tramadol-containing products.

Body as a Whole:Accidental injury,Allergic reaction,Anaphylaxis, Death,Suicidaltendency,Weight loss, Serotonin syndrome (mental status change, hyperreflexia,fever, shivering,tremor, agitation, diaphoresis,seizuresandcoma).

Cardiovascular:Orthostatic hypotension,Syncope, Tachycardia.

Central Nervous System:Abnormal gait,Amnesia, Cognitive dysfunction,Depression,注意力不集中,Hallucinations, Paresthesia,Seizure,Tremor．

Respiratory:Dyspnea.

Skin:Stevens-Johnson syndrome/Toxic epidermal necrolysis,Urticaria, Vesicles.

Special Senses:Dysgeusia.

Urogenital:Dysuria, Menstrual disorder.

Other Adverse Experiences, Causal Relationship Unknown

A variety of other adverse events were reported infrequently in patients taking Ultram during clinical trials and/or reported in post-marketing experience. A causal relationship between Ultram and these events has not been determined. However, the most significant events are listed below as alerting information to the physician.

Cardiovascular:AbnormalECG,Hypertension,Hypotension, Myocardial ischemia,Palpitations,Pulmonary edema,Pulmonary embolism．

Central Nervous System:Migraine．

Gastrointestinal:Gastrointestinal bleeding,Hepatitis, Stomatitis,Liverfailure.

Laboratory Abnormalities:Creatinineincrease, Elevatedliver enzymes,Hemoglobindecrease,Proteinuria．

Sensory:Cataracts, Deafness,Tinnitus．

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of Ultram. 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.

雄激素deficiency:Cases ofandrogendeficiency have occurred with chronic use of opioids.

QT prolongation/torsade de pointes:Cases of QT prolongation and/ortorsade de pointeshave been reported with tramadol use. Many of these cases were reported in patients taking another drug labeled for QT prolongation, in patients with a risk factor for QT prolongation (e.g.,hypokalemia), or in the overdose setting.

Eye disorders- mydriasis

Metabolism andnutritiondisorders- Cases ofhypoglycemiahave been reported very rarely in patients taking tramadol. Most reports were in patients with predisposing risk factors, includingdiabetesor renal insufficiency, or in elderly patients.

Nervous system disorders- movement disorder, speech disorder

Psychiatric disorders-delirium

Table 2: Clinically SignificantDrug Interactionswith Ultram

Inhibitors of CYP2D6
Clinical Impact:	随之而来的CYP2D6片剂和抑制剂的使用s 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 Ultram is achieved. Since M1 is a more potent μ-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. This could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity, such as potentially fatal respiratorydepression．
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 Ultram 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 Ultram 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 respiratorydepression, particularly when an inhibitor is added after a stable dose of Ultram 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 or a withdrawal syndrome in patients who had developed physical dependence to tramadol.
Intervention:	If concomitant use is necessary, consider dosage reduction of Ultram 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 Ultram 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)
CYP3A4 Inducers
Clinical Impact:	The concomitant use of Ultram 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.
Intervention:	If concomitant use is necessary, consider increasing the Ultram dosage until stable drug effects are achieved. Follow patients for signs of opioid withdrawal. If a CYP3A4 inducer is discontinued, consider Ultram 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 Ultram 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, increases the risk of 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 othersedatives/hypnotics, anxiolytics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opioids, and alcohol.
Serotonergic Drugs
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 Ultram immediately 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 aslinezolidand intravenousmethylene blue).
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact:	MAOIinteractions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g., respiratory depression, coma).
Intervention:	Do not use Ultram 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 Ultram and/or precipitate withdrawal symptoms.
Intervention:	Avoid concomitant use.
Examples:	butorphanol,nalbuphine, pentazocine, buprenorphine
Muscle Relaxants
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 Ultram and/or the muscle relaxant as necessary.
Diuretics
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.
Anticholinergic Drugs
Clinical Impact:	The concomitant use of anticholinergic drugs may increase risk ofurinary retentionand/or severeconstipation, which may lead to paralytic ileus.
Intervention:	Monitor patients for signs of urinary retention or reduced gastric motility when Ultram is used concomitantly with anticholinergic drugs.
Digoxin
Clinical Impact:	曲马多的上市后监测ed rare reports ofdigoxintoxicity.
Intervention:	Follow patients for signs of digoxin toxicity and adjust dosage of digoxin as needed.
Warfarin
Clinical Impact:	曲马多的上市后监测ed rare reports of alteration ofwarfarineffect, 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.

控制物质

Ultram (tramadol hydrochloride) contain tramadol, a Schedule IV controlled substance.

Abuse

Ultram contains tramadol, a substance with a high potential for abuse similar to other opioids. Ultram 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, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Prescriptiondrug abuseis the intentional non-therapeutic use of a prescription drug, even once, for its rewarding psychological or physiological effects.

Drug addictionis 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 todrug usethan 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 adequatepainrelief can be appropriate behavior in a patient with poor pain control.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Healthcare 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.

Ultram, 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 Ultram

Ultram is intended for oral use only. Abuse of Ultram poses a risk of overdose and death. The risk is increased with concurrent abuse of Ultram with alcohol and other central nervous system depressants.

Parenteraldrug abuseis commonly associated with transmission of infectious diseases such ashepatitisandHIV．

Dependence

Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of drugs 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 (pentazocine,butorphanol,nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.

Ultram should not be abruptly discontinued in a physically-dependent patient. If Ultram 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官网地址bwin, 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.