Tramadol (Dosing, Interaction, Side Effect, Administration, Etc..)

Dosing:

Adult Dose

:
Important Note:
Beers Criteria:
Use caution or

avoid use

as potentially inappropriate in older adults.

Orphan drug designation:
Treatment of painful HIV-associated neuropathy
Management of postherpetic neuralgia

Dental pain:
50; 70; or 100 mg orally as a

single dose

Pain; chronic; moderate to moderately severe in patients requiring around-the-clock treatment for an extended period of time:

Extended-release tablets

for patients not currently on tramadol immediate-release products:
100 mg orally once daily; may titrate up by 100-mg increments every 2 to 3 days as necessary; maximum 300 mg/day.

Extended-release tablets or capsules for patients not currently on tramadol immediate-release products:
100 mg orally once daily; may titrate up by 100-mg increments every 5 days as necessary; maximum 300 mg/day.

Extended-release tablets or capsules; for patients currently on tramadol immediate-release products (IR):
Calculate 24-hour tramadol

IR dose

and initiate a total

daily dose

rounded down to the nearest 100-mg increment; maximum 300 mg/day.

Pain (Moderate to Severe):

Tramadol hydrochloride

oral disintegrating tablets

have been discontinued from the market.

Pain (Moderate to Severe); Not responsive to non-narcotic analgesics:
(

Immediate-release tablets

)
Initial; 25 mg/day orally every morning; titrated in 25-mg increments as separate doses every 3 days to reach 100 mg/day (25 mg 4 times daily); may increase total daily dose by 50 mg every 3 days as tolerated to reach 200 mg/day (50 mg 4 times daily)

(Immediate-release tablets)
Maintenance; 50 to 100 mg orally every 4 to 6 hours as needed following initial titration; maximum 400 mg/day

(Immediate-release tablets)
Rapid analgesic onset; 50 to 100 mg orally every 4 to 6 hours as needed without initial titration; maximum 400 mg/day

(Immediate-release tablets)
Discontinuation; decrease

dose

by 25% to 50% every 2 to 4 days; if signs or symptoms of withdrawal develop; raise the dose and taper more slowly

Pediatric Dose

:
Important Note:
Beers Criteria:
Use caution or avoid use as potentially inappropriate in older adults.

Orphan drug designation:
Treatment of painful HIV-associated neuropathy
Management of postherpetic neuralgia

General Dosage Information:
(Immediate-release tablets;

extended release tablets

and capsules) Safety and efficacy in pediatric patients have not been established
Life-threatening respiratory depression and death have occurred in children who received tramadol. Death was most often associated with post-tonsillectomy or adenoidectomy; especially in patients who were ultra-rapid metabolizers of codeine (i.e.; multiple copies of the gene for CYP2D6). Children with sleep apnea may be especially sensitive to the respiratory depressant

effects of tramadol

Use is contraindicated for all children younger than 12 years
Use is contraindicated for postoperative pain management in pediatric patients of any age undergoing tonsillectomy and/or adenoidectomy
Avoid use in adolescents 12 to 18 years who have risk factors that may increase the respiratory depressant effects of tramadol. Risk factors include postoperative status; obstructive sleep apnea; obesity and other conditions associated with hypoventilation syndromes; concomitant

use of

other medications that cause respiratory depression; and severe pulmonary disease
Use the

lowest effective dose

for the shortest amount of time and inform patients and caregivers about the risks and signs of

opioid overdose

Pain (Moderate to Severe); Not responsive to non-narcotic analgesics:
(Immediate-release tablets; 17 years and older)
Initial; 25 mg/day orally every morning; titrated in 25mg increments as

separate doses

every 3 days to reach 100 mg/day (25 mg 4 times daily); may increase total daily dose by 50 mg every 3 days as tolerated to reach 200 mg/day (50 mg 4 times daily)

(Immediate-release tablets; 17 years and older):
Maintenance; 50 to 100 mg orally every 4 to 6 hours as needed following initial titration; maximum 400 mg/day

(Immediate-release tablets; 17 years and older):
Rapid analgesic onset; 50 to 100mg orally every 4 to 6 hours as needed without initial titration; maximum 400 mg/day

(Immediate-release tablets; 17 years and older):
Discontinuation;

decrease dose

by 25% to 50% every 2 to 4 days; if signs or symptoms of withdrawal develop; raise the dose and taper more slowly

(12 years or older):
Contraindicated if

used for

postoperative pain management of tonsillectomy and/or adenoidectomy

Indications:
FDA-LABELED INDICATIONS:
Dental pain
Pain; chronic; moderate to moderately severe in patients requiring around-the-clock treatment for an extended period of time
Pain (Moderate to Severe)
Pain (Moderate to Severe); Not responsive to non-narcotic analgesics

NON FDA-LABELED INDICATIONS:
Anesthesia; Adjunct
Cancer pain

Mechanism Of Action:

Tramadol HCl

is a centrally-acting synthetic opioid analgesic that exerts its effect through the binding of parent drug and O-desmethyl-tramadol (M1) metabolite to mu-opioid receptors and through the weak inhibition of norepinephrine and serotonin reuptake

Adverse Effect:
Common:
Dermatologic:
Flushing (7.7% to 15.8%)
Pruritus (3% to 11.9%)

Gastrointestinal:
Constipation (10% to 46%)
Nausea (13% to 40%)
Vomiting (3% to 17%)
Xerostomia (1% to 10%)

Neurologic:
Dizziness (7% to 33%)
Headache (3% to 32%)
Insomnia (1% to 10.9%)
Somnolence (4% to 25%)

Serious
Cardiovascular:
Myocardial infarction (0.5% to less than 1%)

Endocrine metabolic:
Hypoglycemia (Very rare)

Gastrointestinal:
Pancreatitis (0.5% to less than 1%)

Immunologic:
Anaphylactoid reaction (less than 1%)

Neurologic:
Seizure

Respiratory:
Difficulty breathing
Dyspnea (less than 5%)
Respiratory depression

Other:
Serotonin syndrome (Less than 1%)

Contraindication:
Significant respiratory depression in unmonitored settings or without resuscitative equipment
Acute intoxication with alcohol; hypnotics; narcotics; centrally acting analgesics; opioids; or psychotropic drugs; may worsen CNS and respiratory depression
Acute or severe bronchial asthma; in unmonitored settings or without resuscitative equipment Children younger than 12 years
Postoperative management in children younger than 18 years of age following tonsillectomy and/or adenoidectomy

Hypercapnia:
Hypersensitivity to Opioids; tramadol hydrochloride; or any other components of the product
Known or suspected gastrointestinal obstruction; including paralytic ileus.,
Concurrent use of monoamine oxidase inhibitors (MAOIs) or use of MAOIs with the last 14 days

Interaction:
Inhibitors of CYP2D6:
The concomitant

use of tramadol

hydrochloride 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 tramadol hydrochloride

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 which could increase or prolong therapeutic effects but also increase adverse reactions related to opioid toxicity; and may cause potentially fatal respiratory depression

Inhibitors of CYP3A4:
The concomitant

use of tramadol hydrochloride

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 tramadol hydrochloride

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.

CYP3A4 Inducers:
The concomitant

use of tramadol

hydrochloride 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 induc
er decline; the tramadol plasma concentration will increase which could increase or prolong both the therapeutic effects and adverse reactions; and may cause seizures and serotonin syndrome; and potentially fatal respiratory depression

Benzodiazepines and Other Central Nervous System (CNS) Depressants:
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.

Examples: Benzodiazepines and other sedatives/hypnotics; anxiolytics; tranquilizers; muscle relaxants; general anesthetics; antipsychotics; other opioids; alcohol

Serotonergic Drugs:
The concomitant

use of opioids

with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome

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):
MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity (e.g.; respiratory depression; coma)
Examples: phenelzine; tranylcypromine; linezolid

Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics:
May reduce the

analgesic effect of tramadol

hydrochloride and/or precipitate withdrawal symptoms Examples: butorphanol; nalbuphine; pentazocine; buprenorphine

Muscle Relaxants:
Tramadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression

Diuretics:
Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone

Anticholinergic Drugs:
The concomitant use of anticholinergic drugs may increase risk of urinary retention and/or severe constipation; which may lead to paralytic ileus

Digoxin:
Post-marketing surveillance of tramadol has revealed rare reports of digoxin toxicity

Warfarin:
Post-marketing surveillance of tramadol has revealed rare reports of alteration of warfarin effect; including elevation of prothrombin times

Phamacokinetics:
Absorption:
Oral:
Time for Maximum Plasma Concentration (Tmax):
1 to 2.3 hours
Geriatrics: 2.1 hours
Hepatic impairment: 1.9 hours
Extended-release capsules/tablet: 4 to 12 hours

Bioavailability:
Immediate-release tablet: 75%
Extended-release tablet: approximately 85% to 95% relative to immediate-release tablet

Effects of food:
Immediate-release tablet: None
Orally-disintegrating tablet: delayed Tmax; rate and extent of absorption not affected
Extended-release tablet: Cmax increased 54% to 67%; but AUC not affected
Extended-release capsule: None
Extended-release tablet: AUC decreased 28%; Cmax decreased 16%; Tmax increased 3 hours

Distribution:
Plasma Protein binding: Approximately 20%

Volume of Distribution (Vd):
Female: 2.9 L/kg
Male: 2.6 L/kg

Metabolism:
Hepatic: extensive via CYP2D6 and CYP3A4; conjugation; N and O demethylation; and glucuronidation or sulfation

O desmethyl tramadol (M1):active
Substrate of CYP3A4 and CYP2D6.

Excretion:
Renal:
60% as metabolite
Approximately 30% unchanged.

Dialyzable:
Less than 7% removed over 4 hours.
Hemodialysis: No

Total body clearance:
Adults: 5.9 mL/min/kg
Elderly: 6.89 mL/min/kg
Hepatic impairment: 4.23 mL/min/kg
Oral disintegrating tablet; renal impairment: 3.73 to 4.23 mL/min/kg

Elimination:
Immediate-release: adults; 5.6 to 6.7 hours
Extended-release: 6.5 to 10 hours

Immediate-release:
Geriatric (aged 75 years and older); 7 hours
Hepatic impairment; 13 hours
IV: renal impairment (CrCl less than 30 mL/min); 10.6 hours to 11 hours.
O-desmethyl-tramadol (M1);
Immediate-release: 6.7 to 7 hours
Extended-release: 7.5 to 11 hours
Immediate-release: hepatic impairment; 18.5 to 19 hours
IV: renal impairment (CrCl less than 30 mL/min); 11.5 to 16.9 hours

Precaution:
Beers Criteria:
Avoid

use in older patients

with chronic seizures or epilepsy as seizure threshold may be decreased. Avoid use in older patients with a history of falls or fractures as ataxia; impaired psychomotor function; syncope and falls may occur (excludes patients requiring pain management due to recent fractures or joint replacement). If use is necessary; consider reducing use of other CNS-active agents that increase risk of falls and fractures and implement other strategies to reduce risk of falls.

Addiction:
High risk of abuse; addiction; or misuse; especially in patients with a personal or family history of substance abuse or mental illness; monitoring recommended

Cardiovascular:
Severe hypotension and syncope may occur; with increased risk in patients whose ability to maintain blood pressure has been compromised or with concurrent administration of certain central nervous system depressants; monitoring recommended; especially at start of therapy and during dosage adjustments
Circulatory shock; avoid use.

Concomitant use:
Avoid alcohol
Carbamazepine is not recommended
Avoid use with agonist/antagonist or partial agonist analgesics.

Endocrine and metabolic:
Opioids may rarely lead to adrenal insufficiency due to inadequate amounts of cortisol. If adrenal insufficiency is suspected; perform diagnostic testing; treat with corticosteroids if confirmed; wean patient off of opioid if appropriate; and continue to assess adrenal function.

Gastrointestinal:
Use caution in patients with acute abdominal conditions as clinical course may be obscured Spasm of the sphincter of Oddi may occur; monitoring recommended in patients with biliary tract disease; including pancreatitis.

Hepatic:
Cirrhosis;

dose adjustment

may be necessary
Use caution in patients with any degree Tramadol hepatic impairment; use not recommended for tramadol hydrochloride extended-release.

Immunologic:
Anaphylactoid reactions; including serious and rarely fatal reactions often following the

first dose

; have been reported.

Misuse or abuse:
Potential for abuse; misuse; and diversion exists
History of misuse increases suicide risk.

Neurologic:
Potentially life-threatening serotonin syndrome may occur; particularly with concomitant use of serotonergic drugs
Seizures have been reported; especially with doses exceeding recommended range; with concomitant use of drugs that reduce seizure threshold; in patients with epilepsy; a history of seizures; or other risks for seizures; including head trauma; certain metabolic disorders; alcohol and drug withdrawal; and CNS infections.
Increased intracranial pressure or head injury may result in exaggerated carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure; miosis from

tramadol therapy

may obscure intracranial pathology
Respiratory depression and sedation due to carbon dioxide retention may occur in patients with increased intracranial pressure; brain tumors; and head injury; monitoring recommended; especially at therapy initiation
Impaired consciousness or coma; avoid use.

Prolonged use:
Long-term use of Opioids may be associated with decreased sex hormone levels and symptoms such as reduced interest in sex; impotence; or infertility. Laboratory evaluation may be warranted.

Psychiatric:
Use is not recommended in patients who are suicidal or addiction-prone
Emotional disturbances or depression increases suicide risk.

Renal:
Severe renal impairment (CrCl less than 30 mL/min);

dose reduction

recommended for tramadol hydrochloride immediate-release and

orally disintegrating tablets

(ODT) and use not recommended with extended-release

formulations Tramadol

hydrochloride

Respiratory:
Respiratory depression may occur; with increased risk when

large doses

are administered with anesthetic medications or alcohol; or when

used

concomitantly with CNS depressants; consider alternative non-opioid analgesics.

Special populations:
Ambulatory patients may experience impaired mental or physical abilities; caution advised with potentially hazardous tasks.

Respiratory:
Life-threatening respiratory depression may occur; especially in patients with chronic pulmonary disease; including chronic obstructive pulmonary disease; cor pulmonale; decreased respiratory reserve; hypoxia; hypercapnia; or pre-existing respiratory depression; the elderly; cachectic; or debilitated patients; monitoring recommended; especially at start of therapy and during dosage., adjustments. Consider alternative; non-opioid therapy.

Special populations:
Breastfeeding while receiving

treatment with tramadol

is not recommended; especially in mothers who have the CYP2D6 ultra-rapid metabolizer genotype; due to serious adverse reactions in breastfed infants including sedation or respiratory depression that could result in death

Avoid use

in adolescents between 12 and 18 years of age who are obese or have respiratory conditions (e.g.; obstructive sleep apnea or compromised respiratory function) due to increased risk of respiratory adverse events
Patients over 75 years experience adverse events more frequently; start at low end of dosing range in patients older than 65 years
Phenylketone sensitivity; use of ODT not recommended

Withdrawal:
Abrupt discontinuation may induce withdrawal; taper recommended when discontinuing.

Pregnancy Category:
Fetal Risk cannot be ruled out.

Breast Feeding:
Infant risk has been demonstrated

Monitoring:
Pain reduction; improvement in ability to move

Evaluate maintenance of pain control: Continuously

Hypotension: With therapy initiation and dose adjustments in patients with compromised ability to maintain blood pressure

Increased seizure frequency or severity: In patients with a history of seizure disorder
Signs and symptoms of respiratory depression: Within the first 24 to 72 hours of therapy initiation and after

dose increases

; especially in the elderly; cachectic; debilitated; and those with chronic pulmonary disease or with concomitant use of other drugs that cause respiratory depression

Signs of sedation and respiratory depression: During therapy initiation in patients susceptible to intracranial effects of carbon dioxide retention (e.g.; pre-existing intracranial pressure; brain tumors; or head injuries)
Suicidal ideation or worsening depression

How To Take Or Administration:
Oral:
(Immediate-release tablets)
May be taken with or without food

(Extended-release tablets or capsules)
Do not crush, chew, or split; may be taken with or without food

Dosage Form:
Oral Capsule; Extended Release:
100 MG
150 MG
200 MG

Oral Tablet:
50 MG

Oral Tablet; Extended Release:
100 MG
200 MG
300 MG

Treatment:
MANAGEMENT OF MILD TO MODERATE TOXICITY:
Patients generally only need observation and supportive care

MANAGEMENT OF SEVERE TOXICITY:
Naloxone is the antidote indicated for significant CNS or respiratory depression. Orotracheal intubation for airway protection should be performed early in cases of obtundation and/or respiratory depression that do not respond to naloxone Treat seizures with benzodiazepines

Toxicology:
ADULTS:
In adults; 500 mg was the

lowest dose

associated with seizures; respiratory depression; agitation; tachycardia or hypertension. Adult fatalities have been reported after ingestion of 2.65 to 8.2 g tramadol without coingestants. An adult with a

tramadol overdose

developed a Brugada ECG pattern. An adult survived an estimated maximal ingestion of 10 g, but had a residual moderate cerebral deficit.

PEDIATRIC:
A teenager developed multiorgan dysfunction after ingesting

6 g of tramadol

, but recovered completely. Children have tolerated ingestions of up to 300 mg with mild toxicity; but experience is limited. Serotonin syndrome was observed in an 8-month old after ingesting

200 mg of tramadol

; recovery was uneventful. Severe toxicity has been reported in infants who received 100 mg rectally

Patient Counselling Or Clinical Teaching:
Tell patient to report symptoms of respiratory depression
Counsel patient to report symptoms of adrenal insufficiency
Instruct patient to avoid activities requiring mental alertness or coordination until drug effects are realized; as this drug may cause dizziness; somnolence; and impaired mental and physical abilities

Side effects

may include pruritus; dizziness; diarrhea; nausea; vomiting; headache; seizures; and rarely hallucinations
Tell patient to report symptoms of hypotension or syncope
Instruct patient; family members; and caregivers to report worsening depression; suicidal ideation; or unusual changes in behaviour
Advise patient to report symptoms of serotonin syndrome
Tell patient to report severe constipation
Advise patient against sudden discontinuation of drug; as this may precipitate withdrawal symptoms
Advise patient to avoid alcohol and other CNS depressants while taking this drug




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