Tramadol (Systemic)


VA CLASSIFICATION
Primary: CN103

Commonly used brand name(s): Ultram.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Analgesic—

Indications

Accepted

Pain (treatment)—Tramadol is indicated for the management of moderate to moderately severe pain {01}. It has been used to treat pain following orthopedic and gynecological procedures, including cesarean section {01} {06} {24} {32} {36}.

Acceptance not established
Tramadol has been used for long-term treatment of chronic pain such as low back pain, neuropathic pain, orthopedic and joint conditions, and cancer pain {16} {31}. Tramadol may be a therapeutic option for patients who are intolerant to or inappropriate candidates for nonsteroidal anti-inflammatory drugs (NSAIDs); however, more studies evaluating safety and efficacy need to be established for long-term use {11} {30}.

Tramadol has been evaluated and has shown promise as an adjunct to NSAIDs for patients experiencing inadequate relief from dental pain with NSAIDs alone {24}. Although tramadol would not be effective in patients needing only anti-inflammatory treatment, it would be effective in enhancing the suppression of pain {24}. A small study found a single dose of tramadol given concomitantly with a single dose of ibuprofen enhanced suppression of dental pain caused by inflammation. However, additional studies need to be done to evaluate the use of tramadol and NSAIDs concomitantly as a therapeutic combination to enhance analgesic efficacy {03} {24}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Synthetic {01}
Molecular weight—
    299.84 {07}

pKa—
    9.41 {01}

Mechanism of action/Effect:

Tramadol is a centrally-acting synthetic opioid{40}analgesic {01}. The mechanism of action of tramadol is not completely understood, but it may bind to mu-opioid receptors and inhibit the reuptake of norepinephrine (NE) and serotonin {01}. The ability of tramadol to inhibit the neuronal uptake of monoamines in the same concentration range at which it binds to mu-opioid receptors differentiates it from typical opioids {05}. Tramadol consists of (+) and (-) enantiomers that appear to interact synergistically to produce antinociception {05}. The (+) enantiomer is fivefold more potent in 5- hydroxytryptamine (5-HT) uptake and has a greater affinity for mu receptor binding than for NE uptake {05}. The (-) enantiomer is five- to tenfold more potent in NE uptake inhibition and has less affinity for mu receptor binding than for 5-HT uptake {05}. Electrophysiological studies show that tramadol, like morphine, depresses motor and sensory responses of the spinal nociceptive system by a spinal and a supraspinal action {18}. Some opioid activity is derived from low-affinity binding of the parent compound and higher-affinity binding of the mono- O-desmethyltramadol (M1) metabolite to the opioid receptors {01}. The analgesic potency of M1 is about six times greater than that of tramadol in animal models and 200 times more potent in mu-opioid receptor binding {01}.

Note: It has been estimated that the analgesic potency of tramadol is one-tenth that of morphine {28}.



Other actions/effects:

Tramadol suppresses the cough reflex by binding to the mu-opioid receptor binding sites {10}. Due to the high affinity binding of the M1 metabolite to the mu receptor, the metabolite has been found to have more cough suppressant activity than the parent compound {10}.

Unlike morphine, tramadol has not been shown to cause histamine release {01} {08}.

Absorption:

Oral—Rapid and almost complete {01}. Mean absolute bioavailability of a 100-mg dose is approximately 75% {01}. The rate or extent of absorption is not significantly affected by administration with food {01} {27}.

Distribution:

The volume of distribution is 2.6 and 2.9 liters per kilogram of body weight (L/kg) in males and females, respectively, following a 100-mg intravenous dose {01}. Tramadol crosses the blood-brain barrier in rats and possibly in humans {01} {26}. In women given tramadol during labor, the mean ratio of tramadol concentration in the umbilical veins compared to maternal veins was 0.83 {01}.

Protein binding:

Low (20%) {01}. Independent of concentration up to 10 micrograms per mL (mcg/mL); saturation of binding occurs only at concentrations outside of the clinically relevant range {01}.

Biotransformation:

Hepatic. Extensively metabolized via N- and O-demethylation and glucuronidation or sulfation {01}. The production of the active metabolite mono- O-desmethyltramadol (M1) is dependent on the CYP2D6 isoenzyme of cytochrome P450 {01}. The inactive metabolites are formed by N-demethylation {19}.

Half-life:


Terminal:


Individuals with normal renal function—

Tramadol—Approximately 6.3 hours (increased to 7 hours with multiple dosing [not clinically significant] and in individuals over 75 years of age [clinically significant]) {01}.

M1 metabolite—Approximately 7.4 hours {01}.



Onset of action:

Dose-dependent; generally within 1 hour {01}.

Time to peak concentration:


Plasma:


Following a single 100-mg dose—

Tramadol—2 hours {01}.

M1 metabolite—3 hours {01}.



Time to steady state concentration


Plasma:


After administration of 100 mg four times a day—

About 2 days {01}.



Peak serum concentration:


Plasma:


Following a single 100-mg dose—

Tramadol—308 nanograms per mL ±78 nanograms/mL {01}.

M1 metabolite—55 nanograms/mL ± 20 nanograms/mL {01}.



Time to peak effect:

Tramadol—2 hours {01}.

M1 metabolite—3 hours {01}.

Elimination:


Renal—
        30% unchanged; 60% as metabolites. Clearance rate is slightly higher in females than in males {01}.



In dialysis—
        7% of an administered dose is removed by hemodialysis {01}.



Precautions to Consider

Tumorigenicity

Evidence of a statistically significant increase in two common murine tumors (pulmonary and hepatic) was observed in mice receiving oral doses up to 30 mg per kg of body weight (mg/kg) for approximately 2 years {01}. However, no tumors were observed in a rat carcinogenicity study {01}.

Mutagenicity

No evidence of mutagenicity was found in the Ames test, CHO/HPRT mammalian cell assay, mouse lymphoma assay, dominant lethal mutation test in mice, chromosome aberration test in Chinese hamsters, or bone marrow micronucleus tests in mice and Chinese hamsters {01}. Weakly mutagenic results occurred in the presence of metabolic activation in the mouse lymphoma assay and micronucleus test in rats {01}.

Pregnancy/Reproduction
Fertility—
No impairment of fertility was observed at oral dose levels up to 50 mg/kg in male rats and 75 mg/kg in female rats {01} {21}.

Pregnancy—
Tramadol has been shown to cross the placenta {01}. Well-controlled studies in humans have not been done {01}.

Studies have shown tramadol to be embryotoxic and fetotoxic in mice, rats, and rabbits at maternally toxic doses (3 to 15 times the maximum human dose or higher); however, it was found not to be teratogenic at these levels. Studies done in progeny of mice, rats, and rabbits given tramadol by various routes (up to 140 mg/kg for mice, 80 mg/kg for rats, or 300 mg/kg for rabbits) found no drug-related teratogenic effects. Transient delays in the developmental and behavioral parameters during the delivery of pups from rat dams were observed. At maternally toxic levels, fetal toxicity and embryotoxicity primarily included decreased fetal weights, skeletal ossification, and increased supernumerary ribs. A study in rabbits reported embryo and fetal lethality caused by extreme maternal toxicity at doses of 300 mg/kg. In peri- and postnatal studies in rats, decreased weights were observed in the progeny of dams that received oral (gavage) doses of 50 mg/kg or greater. At doses of 80 mg/kg (6 to 10 times the maximum human dose), pup survival was decreased early in lactation. The progeny of dams receiving 8, 10, 20, 25, or 40 mg/kg showed no signs of toxicity. Evidence of severe maternal toxicity was observed at higher doses; however, maternal toxicity was found at all dose levels {01}.

FDA Pregnancy Category C {01}.


Labor and delivery—

Tramadol is not recommended for use in pregnant women prior to or during labor unless the potential benefits outweigh the risks, because safe use in pregnancy has not been established {01}. Long-term use of tramadol during pregnancy may lead to physical dependence and postpartum withdrawal symptoms in the newborn {01}.

Breast-feeding

Following a single intravenous 100-mg dose of tramadol, the cumulative distribution in breast milk within 16 hours postdose was 100 micrograms (mcg) of tramadol (0.1% of the maternal dose) and 27 mcg of M1 {01}. Use of oral tramadol is not recommended for obstetrical preoperative medication or postdelivery analgesia in nursing mothers because of lack of studies on its safety in infants and newborns {01}.

Pediatrics

No information is available on the relationship of age to the effects of tramadol in patients under 16 years of age {01}. Safety and efficacy have not been established {01}.


Geriatrics


Studies have shown that, in subjects over the age of 75 years, serum concentrations are slightly elevated and the elimination half-life is slightly prolonged {01}. In addition, elderly patients are more likely to have age-related renal function impairment that may require dosage adjustment.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

» Alcohol or
» Anesthetic agents or
» Central nervous system (CNS) depression–producing medications, other (see Appendix II ), such as:
Antidepressants, tricyclics
Opioid analgesics
Phenothiazines
Sedative hypnotics
Tranquilizers    (caution is recommended because concurrent use may potentiate the CNS depressant effects; tricyclic antidepressants, fluoxetine, and sertraline may increase the risk of seizures; dosage reduction is recommended {01})


» Carbamazepine    (causes a significant increase in tramadol metabolism, presumably through metabolic enzyme induction; dosage adjustment may be required {01} {39} [patients receiving chronic carbamazepine in doses up to 800 mg per day may require up to twice the recommended dose of tramadol] {01})


» Monoamine oxidase (MAO) inhibitors, including furazolidone and procarbazine    (tramadol inhibits the uptake of norepinephrine and serotonin {01}; serotonin is believed to be the biogenic amine responsible for the toxic interactions {04}; concurrent use may decrease seizure threshold; caution is recommended {01})


Quinidine    (concurrent use may increase concentrations of tramadol and decrease concentration of the M1 metabolite by competitively inhibiting the CYP2D6 isoenzyme {01} {12}; inhibition of the formation of the M1 metabolite did not significantly alter the peak analgesic effect of a single 100-mg dose of tramadol in healthy volunteers {01} {19})


Propafenone    (concurrent use may increase concentrations of tramadol and decrease concentration of the M1 metabolite by inhibiting the CYP2D6 isoenzyme {12})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Note: Tramadol does not affect the bile duct sphincter, which indicates that it is less likely than opioids to cause urinary retention, constipation, or worsening of pancreatic or biliary disorders {15}.


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Acute intoxication with alcohol, hypnotics, centrally-acting analgesics, opioids, or psychotropic drugs    (risk of respiratory depression {01})


» Drug abuse or dependence, current or history of, including alcoholism    (patient predisposition to drug abuse)


Risk-benefit should be considered when the following medical problems exist
Acute abdominal conditions{01}    (diagnosis may be obscured)


» Hepatic function impairment    (metabolism of tramadol and M1 is reduced in patients with advanced cirrhosis of the liver; dosage reduction is recommended; delay in achievement of steady state may result from the prolonged half-life in this condition {01})


Increased intracranial pressure or
Head trauma    (tramadol causes pupillary changes [miosis] that may obscure the existence, extent, or course of intracranial pathology; clinicians should consider the possibility of a drug effect when evaluating mental status {01})


» Renal function impairment    (decreased rate and extent of excretion of tramadol and its active metabolite M1; dosage reduction is recommended in patients with creatinine clearance of less than 30 mL per minute [mL/min]; delay in achievement of steady-state may result from the prolonged half-life in this condition {01})


» Respiratory depression, risk of    (tramadol may decrease respiratory drive and increase airway resistance in patients with this condition {30}; although there is absence of significant respiratory depression following epidural and intravenous use {29} {30}, caution is still recommended with administration of oral tramadol in patients at risk for respiratory depression {01}; may also occur with concurrent administration of anesthetic medication or alcohol {01})


» Seizures    (tramadol may increase the risk of seizures in patients taking neuroleptics and other drugs that reduce the seizure threshold {01})


» Sensitivity to opioids or
» Sensitivity to tramadol    (increased risk of anaphylactoid reactions)




Side/Adverse Effects

Note: Tramadol can produce drug dependence of the mu-opioid type and may potentially be abused {01}. Tolerance development, drug-seeking behavior and craving have been associated with the use of tramadol {01}. The active metabolite of tramadol may be responsible for some delay in onset of activity and some extension of the duration of mu-opioid activity {01}. Delayed mu-opioid activity is believed to reduce drug abuse liability {01}. One case has been reported in which a patient developed tolerance to and dependence on oral tramadol (increase in daily dose by 500% over 6 years, from 50 to 300 mg per day) {20}. However, in a 3-week study no tolerance developed to oral tramadol {09} {13} {28}. A few studies found no or very little development of tolerance with parenteral administration of tramadol {09} {13} {28}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence less frequent or rare
    
Abnormal gait{01} (change in walking and balance)
    
allergic reaction{01} (severe redness, swelling, and itching of the skin)
    
amnesia{01} (loss of memory)
    
cognitive dysfunction{01} (trouble performing routine tasks)
    
dyspnea{01} (shortness of breath)
    
hallucinations{01} (seeing, hearing, or feeling things that are not there)
    
orthostatic hypotension{01} (dizziness or lightheadedness when getting up from a lying or sitting position)
    
paresthesia{01} (numbness, tingling, pain, or weakness in hands or feet)
    
seizures{01}
    
syncope{01} (fainting)
    
tachycardia{01} (fast heartbeat)
    
tremor{01} (trembling and shaking of hands or feet)
    
urinary frequency{01} (frequent urge to urinate)
    
urinary retention{01} (difficult urination)
    
urticaria{01} (redness, swelling, and itching of the skin)
    
vesicles{01} (blisters under the skin)
    
visual disturbances{01} (blurred vision)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Abdominal or stomach pain{01}{33}
    
anorexia{01}{33} (loss of appetite)
    
asthenia{01} (loss of strength or weakness)
    
central nervous system (CNS) stimulation (agitation; anxiety; nervousness; spasticity; unusual feeling of excitement)
    
constipation{01}{06}{31}{33}
    
diarrhea{01}
    
dizziness or vertigo{01}{06}{24}{31}{33}{36}
    
drowsiness{01}{33}
    
dry mouth{01}{32}
    
dyspepsia{01}{33} (heartburn)
    
headache{01}{31}{33}
    
nausea{01}{33}
    
pruritus{01} (itching of the skin)
    
skin rash{01}{33}
    
sweating{01}{33}{36}
    
vomiting{01}{06}{24}{32}{33}
Note: Tramadol may produce opioid-like effects, including constipation, dizziness, drowsiness, nausea, pruritus, and sweating {01}, but causes less respiratory depression than morphine {01}.



Less frequent or rare
    
Confusion{01}
    
depression
    
flatulence{01} (excessive gas)
    
malaise{01}{31}{32} (general feeling of bodily discomfort)
    
menopausal symptoms{01} (hot flashes)
    
sleep disorder{01} (trouble in sleeping)
    
vasodilation (flushing or redness of the skin)



Those indicating possible withdrawal and the need for medical attention if they occur after medication is discontinued
    
Anxiety{20}
    
body aches
    
diarrhea
    
fast heartbeat
    
fever, runny nose, or sneezing
    
gooseflesh
    
hypertension{20} (high blood pressure)
    
increased sweating
    
increased yawning
    
loss of appetite
    
nausea or vomiting
    
nervousness, restlessness, or irritability
    
shivering or trembling
    
stomach cramps
    
trouble in sleeping
    
unusually large pupils
    
weakness{22}{38}
Note: The signs and symptoms of withdrawal listed above are characteristics of the abstinence syndrome produced by abrupt discontinuation of a mu-receptor agonist {38}. Tramadol does have some activity involving the mu- receptor {01}; therefore, abrupt discontinuation may include some of these signs and symptoms {01} {08}. However, these effects may be milder compared with opiate agonists {35}. Tapering the dose of tramadol may prevent some of the signs and symptoms of withdrawal from occurring {01}. Minimal withdrawal signs have been observed in naloxone-precipitation studies {02}.






Overdose
For specific information on the agents used in the management of tramadol overdose, see:

   • Diazepam in Benzodiazepines (Systemic) monograph; and/or
   • Naloxone (Systemic) monograph {01}.For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
The following effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Acute and chronic effects {23}
    
Cold, clammy skin
    
confusion
    
convulsions{27}
    
dizziness, severe
    
drowsiness, severe
    
nervousness or restlessness, severe
    
pinpoint pupils of eyes{27}
    
slow heartbeat
    
seizures{01}{20}
    
slow or troubled breathing{27}
    
weakness, severe


Note: Studies have found the administration of intravenous tramadol may produce respiratory depression. However, morphine causes more clinically significant respiratory depression than tramadol {30}. Clinical studies evaluating oral doses have not reported any clinically relevant respiratory depressant effects {09} {25} {36}.


Treatment of overdose


To decrease absorption:
Gastric lavage may be performed {27}.



Specific treatment:
Administration of the opioid antagonist naloxone, which will reverse some, but not all, symptoms caused by overdosage with tramadol {01}. Administer naloxone with caution because it may precipitate seizures. See the package insert or Naloxone (Systemic) for specific dosing guidelines for use of this product.

For treatment of convulsions caused by tramadol toxicity: Diazepam has been effective in treating convulsions {27}. See the package insert or Diazepam in Benzodiazepines (Systemic) for specific dosing guidelines for use of this product.



Supportive care:
Supportive measures such as establishing intravenous lines, hydration, correction of electrolyte imbalance, oxygenation, and support of ventilatory function are essential for maintaining the vital functions of the patient {38}. Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.


Note: Hemodialysis is not recommended in overdose, since it removes less than 7% of the administered dose in a 4-hour dialysis period.



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Tramadol (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to tramadol or opioids

Pregnancy—Crosses the placenta; safe use in pregnancy has not been established {01}





Breast-feeding—Distributed into breast milk; use is not recommended
Other medications, especially carbamazepine, CNS depressants or anesthetic agents, or MAO inhibitors
Other medical problems, especially acute intoxication with alcohol, hypnotics, centrally-acting analgesics, opioids, or psychotropic drugs; hepatic function impairment; physical dependence on opioids; renal function impairment; risk of respiratory depression; or seizures

Proper use of this medication
» Not increasing dose if medication is less effective after a few weeks; checking with physician first

» Importance of not taking more medication than the amount prescribed because of danger of overdose

» Proper dosing
Missed dose (if on scheduled dosing): Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Avoiding use of alcoholic beverages or other CNS depressants during therapy unless prescribed or otherwise approved by physician

» Caution if dizziness, drowsiness, or lightheadedness occurs

» Caution when getting up from a lying or sitting position

Lying down if nausea or vomiting, or dizziness or lightheadedness occurs

Informing physician or dentist of use of medication if any kind of surgery (including dental surgery) or emergency treatment is required

» Suspected overdose: Getting emergency help at once


Side/adverse effects
Signs of potential side effects, especially abnormal gait, allergic reaction, amnesia, cognitive dysfunction, dyspnea, hallucinations, orthostatic hypotension, paresthesia, seizures, syncope, tachycardia, tremor, urinary frequency, urinary retention, urticaria, vesicles, and visual disturbances


Oral Dosage Forms

TRAMADOL HYDROCHLORIDE TABLETS

Usual adult and adolescent dose
Analgesic—Oral, 25{40} to 100 mg every four to{40} six hours as needed {01}.

Note: In patients with moderate to moderately severe chronic pain not requiring rapid onset of analgesic effect, the tolerability of tramadol can be improved by initiating therapy with the following titration regimen: tramadol should be started at 25 mg once daily in the morning and titrated in 25 mg increments as separate doses every 3 days to reach 100 mg daily (25 mg four times a day). Thereafter, the total dose may be increased by 50 mg as tolerated every 3 days to reach 200 mg daily (50 mg four times a day). After titration, tramadol 50 to 100 mg can be administered as needed for pain relief every four to six hours.{40}
In patients needing rapid onset of analgesic effect, the higher 50 to 100 mg initial dose may be warranted if the benefits outweigh the risk of discontinuation due to adverse events associated with higher initial doses.{40}.
Patients with impaired renal function (creatinine clearance less than 30 mL/minute [mL/min]) should receive 50 to 100 mg every twelve hours {01}.
The recommended dose in patients with cirrhosis is 50 mg{40}every twelve hours{40}{01}.
Patients on hemodialysis can receive their usual dose on the day of dialysis{01}.


Usual adult prescribing limits
Oral, 400 mg per day (200 mg per day in patients with creatinine clearance of less than 30 mL/min) {01}.

Usual pediatric dose
Children up to 16 years of age—Safety and efficacy have not been established.

Children 16 years of age and over—See Usual adult and adolescent dose .

Usual geriatric dose
See Usual adult and adolescent dose with consideration that dose selection in patients over 65 years of age should be cautious, usually starting at the low end of the dosing range.{40}.

Usual geriatric prescribing limits
In patients over 75 years of age, the limit is 300 mg per day in divided doses. {40}

Strength(s) usually available
U.S.—


50 mg (Rx) [Ultram (lactose)]

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), in a tight container {01}.

Auxiliary labeling:
   • May cause drowsiness.
   • Avoid alcoholic beverages.

Note: Tramadol is not a controlled substance in the U.S.




Revised: 06/21/2002



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