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Tramadol

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Tramadol is a centrally-acting synthetic opioid analgesic that is not a controlled substance.<ref name=a/> Tramadol is used to treat moderate to moderately severe chronic pain. It can also be used to treat breakthrough pain.<ref name=B/> Tramadol can lower the seizure threshold to a rate of < 1/100,000 (spontaneous seizures), which can be exacerbated by the use of other medications such SSRIs, TCAs, and opioids. Additionally tramadol and sertraline, when given in the same regimen, were found to cause a mild serotonin syndrome.<ref name=sert/> Tramadol does not cause GI bleeding, hypertension or heart failure.

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Chemical structure of Tramadol|{{#ifeq: | mab | | {{#ifeq: | combo | | {{#ifeq: | | }}}}}} }} }}
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Identifiers
CAS number {{#if:27203-92-5 | 27203-92-5 | ? }} {{#if: | }}
ATC code {{#if:N02 | N02{{#if:AX02 | AX02 }} | ? }}
PubChem {{#if:33741 | 33741 | ? }}

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DrugBank APRD00028

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ChemSpider 31105

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SMILES eMolecules & PubChem

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Density {{{density}}} g/cm³

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Therapeutic considerations
Pregnancy cat.

{{#if:C |

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A = A B1 = B1 B2 = B2 B3 = B3 B = B? C = C D = D X = X  ?
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Legal status

{{#if:S4 |

 {{#switch: S4
Unscheduled = Unscheduled | S2 | Schedule 2 = Pharmacy Only (S2) S3 | Schedule 3 = Pharmacist Only (S3) S4 | Schedule 4 = Prescription Only (S4) S5 | Schedule 5 = Caution (S5) S6 | Schedule 6 = Poison (S6) S7 | Schedule 7 = Dangerous Poison (S7) S8 | Schedule 8 = Controlled (S8) S9 | Schedule 9 = Prohibited (S9)  ?
 }}(AU) 

}}{{#if: |

  {{#switch: 
Schedule I = Schedule I Schedule II = Schedule II Schedule III = Schedule III Schedule IV = Schedule IV Schedule V = Schedule V Schedule VI = Schedule VI Schedule VII = Schedule VII Schedule VIII= Schedule VIII  ?
 }}(CA) 

}}{{#if:POM |

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GSL = GSL P =P POM = POM CD =CD Class A = Class A Class B = Class B Class C = Class C  ?
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OTC = OTC Template:Unicode-only | Template:Unicode | rx | Rx | rx-only | Rx-only = [[Prescription drug|Template:Unicode-only]] Schedule I = Schedule I Schedule II = Schedule II Schedule III = Schedule III Schedule IV = Schedule IV Schedule V = Schedule V  ?
 }}(US) 

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RX | Rx | rx-only | Rx-only = Template:Unicode Prescription only
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Dependence Liability {{{dependency_liability}}}

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Routes {{#if:oral, IV, IM, IV, rectal, sublingual, buccal | oral, IV, IM, IV, rectal, sublingual, buccal | ? }}

{{#if: | |}}

There is a small chance of tramadol abuse. The rate is 0.75/100,000 patients and of these, 97% of patients who became addicted had a history of drug and alcohol abuse.<ref name=cicerot>Cicero TJ, Adams EH, Geller A, Inciardi JA, Munoz A, Schnoll SH, et al. A postmarketing surveillance program to monitor Ultram (tramadol hydrochloride) abuse in the United States. Drug and alcohol dependence. 1999 Nov 1;57(1):7-22</ref>

A number of studies have proven the efficacy of tramadol. It is more effective than placebo for osteoarthritis and comparable in efficacy to ibuprofen 2400 mg/day.<ref name=B/> Osteoarthritis is an off-label use. Tramadol was found to be substandard to hydrocodone/acetaminophen for patients entering the emergency department with acute musculoskeletal pain.<ref name=hydroc>Turturro MA, Paris PM, Larkin GL. Tramadol versus hydrocodone-acetaminophen in acute musculoskeletal pain: a randomized, double-blind clinical trial. Ann Emerg Med. 1998 Aug;32(2):139-43.]</ref> Pain relief tyically begins about one hour after administration.<ref name=a/>

Contents

Mechanism of Action

Tramadol is a synthetic analgesic which acts centrally through binding to the opioid µ-receptors and via a tricyclic-like mechanism whereby it inhibits neuronal reuptake of serotonin and norepinephrine within the CNS.<ref name=B>Stitik TP, Altschuler E, Foye PM, Stitik TP, Altschuler E, Foye PM. Pharmacotherapy of osteoarthritis. American Journal of Physical Medicine & Rehabilitation. 2006 Nov;85(11 Suppl):S15-28; quiz S9-31.</ref><ref name=C>Ripple MG, Pestaner JP, Levine BS, Smialek JE. Lethal combination of tramadol and multiple drugs affecting serotonin. Am J Forensic Med Pathol. 2000 Dec;21(4):370-4.</ref> The opioid activity of tramadol is due to tramadol binding to the µ-receptors and the M1 metabolite, which is O-demethylated, binding to the opioid µ-receptors. M1 is 6-times more potent than tramadol when compared for their analgesic qualities. M1 binds to the µ-receptors 200-times stronger than does tramadol. Additionally, tramadol inhibits the reuptake of serotonin and norepinephrine which is believed to contribute to its analgesic properties.<ref name=a/>

Time Required for Therapeutic Response

  • Initial: One hour<ref name=B/>

Pharmacokinetics

Absorption
Tramadol is almost completely absorbed. The bioavailability of a 100 mg dose is 75%. The peak plasma concentrations of racemic tramadol occur 2 hours after the dose. The peak plasma concentrations of M1 occur 3 hours after the dose is given. Steady state is realized 2 days after dosing tramadol four times a day. Food does not impact the rate or extent of absorption.<ref name=a>Ortho-McNeil Pharmaceutical INC. Ultram (tramadol hydrochloride tablets) prescribing information. 2004.</ref>

Distribution
The volume of distribution was 2.6 L/kg in males and 2.9 L/kg in females. Tramadol binds to proteins about 20%. Saturation of plasma proteins is only of concern if one exceeds the recommended dosage.<ref name=a/>

Metabolism
M1 (O-desmethyl-tramadol) is formed by CYP2D6.<ref name= old>Likar R, Wittels M, Molnar M, Kager I, Ziervogel G, Sittl R. Pharmacokinetic and pharmacodynamic properties of tramadol IR and SR in elderly patients: a prospective, age-group-controlled study. Clin Ther. 2006 Dec;28(12):2022-39.</ref> About 7% of the population are considered poor metabolizers of CYP2D6. The concnetrations of tramadol will be about 20% higher in these patients. The M1 concentrations will be about 40% lower when compared to patients who are considered extensive metabolizers of CYP2D6.<ref name=a/> A study looking at poor metabolizers of CYP2D6 versus extensive metabolizers found that for the positive (+) enantiomer, the AUC was 1.98-fold and the negative (-) enantiomer's AUC was 1.74-fold when compared to extensive metabolizers. The oral clearance was examined and was found to be 1.91-fold in poor metabolizers for the (+) enantiomer and 1.71-fold for the negative enantiomer when compared to extensive metabolizers.<ref name=enta>Garcia-Quetglas E, Azanza JR, Sadaba B, Munoz MJ, Gil I, Campanero MA. Pharmacokinetics of tramadol enantiomers and their respective phase I metabolites in relation to CYP2D6 phenotype. Pharmacol Res. 2007 Feb;55(2):122-30.</ref>

Excretion
30% of tramadol will be excreted in the urine unchanged. 60% of the drug will be excreted in the urine as metabolites. The rest is unidentified or is a metabolite which could not be extracted. Tramadol itself is eliminated via the liver. The half-life of tramadol is 6.3 hours and the half-life of M1 is 7.4 hours. After repeated dosing of tramadol, the half-life of tramadol increases to about 7 hours.<ref name=a/>

Special Population Pharmacokinetics

  • Renal insufficiency: Renal insufficiency decreases the rate and extent of elimination of both tramadol and its metabolites. When a patient's creatinine clearance is less than 30 mL/min, a decreased dose of tramadol is recommended, and extended-release tramadol is not recommended.<ref name=a/>
  • Hepatic insufficiency: The metabolism of tramadol is lowered in patients with hepatic insufficiency. This causes a larger area-under the concentration-time curve for tramadol. Tramadol and M1 will have longer elimination half-lives which have been reported to extend to 13 hours for tramadol and 19 hours for M1. Extended-release tramadol is not recommended in this patient population.<ref name=a/>
  • Hemodialysis: After a 4 hour hemodialysis session, less than 7% of the dose of tramadol is cleared from the blood. Extended-release tramadol is not recommended in this patient population.<ref name=a/>
  • Geriatric: In patients over the age of 75, the peak serum concentrations increase from 162 to 208 ng/mL. Additionally, the elimination half-life of tramadol is increased by an hour, from 6 to 7 hours. Based on this pharmacokinetic data, the dosage of tramadol should be adjusted in patients over the age of 75. No PK differences were noted in the population from 65-75 years of age.<ref name=a/> A randomized controlled trial measured serum concentrations of M1 and tramadol in 100 patients. The 100 patients were split up into three groups, greater than or equal to 75 years, 65 to less than 75, and less than 65 years. There were no PK differences between the groups. The group greater than or equal to 75 years used 20% less tramadol than did the group which was less than 65 years of age.<ref name=old/>
  • Pediatric: No data.
  • Gender: The bioavailability was slightly different between males (73%) and females (79%). The plasma clearance was slightly greater in males at 6.4 mL/min/kg vs. 5.7 mL/min/kg in females. Females had a 12% higher peak tramadol concentration than males. Females also had a 35% greater area under the concentration-time curve than did males. Currently, the clinical significance is not known.<ref name=a/>

Indications and Dosages

FDA Approved Indications

Moderate to moderately-severe pain in patients 17 years of age and older<ref name=a/><ref name=chr>Schnitzer TJ, Gray WL, Paster RZ, Kamin M. Efficacy of tramadol in treatment of chronic low back pain. The Journal of rheumatology. 2000 Mar;27(3):772-8.</ref><ref name=com>Moore RA, McQuay HJ. Single-patient data meta-analysis of 3453 postoperative patients: oral tramadol versus placebo, codeine and combination analgesics. Pain. 1997 Feb;69(3):287-94.</ref>

  • Starting dose for chronic pain:
    • 25 mg daily in the morning
  • Starting dose for acute pain:
    • 50 to 100 mg daily every 4 to 6 hours as needed for pain
  • Maintenance dose:
    • 200 mg daily
    • After the titration period is over, additional doses may be given as needed for pain every 4-6 hours.
    • The maximum daily dose is 400 mg (300 mg for ages 75 and up).
  • Titration schedule: titrate in 25 mg increments as separate doses every three days until 25 mg by mouth four times a day is reached. Then the total daily dosage of tramadol may be increased by 50mg every three days to 50 mg by mouth four times a day. Adverse effects will be more likely if tramadol is not titrated.

Non-FDA Approved Indications

  • arthralgia<ref name=arth>Akinci SB, Saricaoglu F, Atay OA, Doral MN, Kanbak M. Analgesic effect of intra-articular tramadol compared with morphine after arthroscopic knee surgery. Arthroscopy. 2005 Sep;21(9):1060-5.</ref>
  • bone pain<ref name=ext>Cander B, Girisgin S, Koylu R, Gul M, Kocak S. The effectiveness of analgesics in traumatic injuries of the extremities. Advances in therapy. 2005 Sep-Oct;22(5):462-6.</ref><ref name=spine>Sekar C, Rajasekaran S, Kannan R, Reddy S, Shetty TA, Pithwa YK. Preemptive analgesia for postoperative pain relief in lumbosacral spine surgeries: a randomized controlled trial. Spine J. 2004 May-Jun;4(3):261-4.</ref>
  • dental pain<ref name=tooth>Moore PA. Pain management in dental practice: tramadol vs. codeine combinations. Journal of the American Dental Association (1939). 1999 Jul;130(7):1075-9.</ref>
  • headache<ref name=headache>Silberstein SD, Freitag FG, Rozen TD, Kudrow DB, Hewitt DJ, Jordan DM, et al. Tramadol/acetaminophen for the treatment of acute migraine pain: findings of a randomized, placebo-controlled trial. Headache. 2005 Nov-Dec;45(10):1317-27.</ref>
  • fibromyalgia<ref name=fib>Bennett RM, Kamin M, Karim R, Rosenthal N. Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study. The American journal of medicine. 2003 May;114(7):537-45.</ref>
  • neuropathic pain<ref name=neuro>Chong MS, Hester J. Diabetic painful neuropathy : current and future treatment options. Drugs. 2007;67(4):569-85.</ref>
  • osteoarthritis<ref name=B/><ref name=OA>Cepeda MS, Camargo F, Zea C, Valencia L. Tramadol for osteoarthritis: a systematic review and metaanalysis. The Journal of rheumatology. 2007 Mar;34(3):543-55.</ref>
  • postoperative shivering<ref name=shi>le Roux PJ, Coetzee JF. Tramadol today. Current opinion in anaesthesiology. 2000 Aug;13(4):457-61.</ref>
  • premature ejaculation<ref name=premature>Salem EA, Wilson SK, Bissada NK, Delk JR, Hellstrom WJ, Cleves MA. Tramadol HCL has Promise in On-Demand Use to Treat Premature Ejaculation. J Sex Med. 2007 Mar 14.</ref>
  • restless legs syndrome <ref name=leg>Vetrugno R, La Morgia C, D'Angelo R, Loi D, Provini F, Plazzi G, et al. Augmentation of restless legs syndrome with long-term tramadol treatment. Mov Disord. 2007 Feb;22(3):424-7.</ref>

Dosage Adjustment

Renal insufficiency: For patients with a CrCl <30 mL/min, the dosage interval should be extended to 12 hours. The maximum daily dose should be lowered to 200 mg/day.<ref name=a/>
Hepatic insufficiency: The recommended dose is 50 mg every 12 hours for patients with hepatic cirrhosis. It is not recommended that patients with hepatic impairment receive extended-release tramadol.<ref name=a/>
Hemodialysis: Patients can receive their regular dose on dialysis days. Only 7% of the dose is removed by a four-hour hemodialysis session. No studies have been completed with hemodialysis patients taking extended-release tramadol, therefore it is not recommended it is given to this patient population.
Geriatric: In patients over the age of 65, dosage should initially be lower than an adult patient. It is be titrated based on tolerability, not to exceed the rate of titration recommended for adult patients. Patients over the age of 75 years, should not exceed 300 mg of tramadol per day.<ref name=a/>
Pediatric: Not indicated.

Dosage Limits

  • Ages 17 to 75: 400 mg/day
  • Elderly over age 75: 300 mg/day
  • Adolescents under age 17 and children: Not indicated


Administration

  • Route: Oral
  • Method:
    • May be taken with or without food. Take with a drink of water or other beverage.
    • Extended-release tablets should be swallowed whole and not crushed or chewed.

Monitoring Parameters

  • Not needed

Contraindications/Precautions

Contraindications

  • Hypersensitivity to tramadol or any of its components
  • Hypersensitivity to opioids
  • Patients acutely intoxicated with alcohol, hypnotics, narcotics, centrally acting analgesics, opioids or psychotropic drugs

Precautions

  • Acute abdominal conditions
  • Renal impairment (caution with immediate-release, extended-release not recommended in severe renal impairment)
  • Hepatic impairment (caution with immediate-release, extended-release not recommended)
  • Respiratory depression
  • Patients receiving anesthetic medications
  • Patients who consume alcohol
  • Patients with epilepsy, a history of seizures, head trauma, metabolic disorder, alcohol withdrawal, drug withdrawal, or CNS infections: seizures may occur with tramadol, even within typical dosage limits. Tramadol can lower the seizure threshold to a rate of < 1/100,000 (spontaneous seizures).<ref name=d>Mason BJ, Blackburn KH. Possible serotonin syndrome associated with tramadol and sertraline coadministration. The Annals of pharmacotherapy. 1997 Feb;31(2):175-7.</ref> Risk of seizures increases when the following drugs are used concomitantly: selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), tricyclic compounds (cyclobenzaprine, promethazine), opioids, monoamine oxidase inhibitors (MAOIs), neuroleptics, alcohol,<ref name=f>Jovanovic-Cupic V, Martinovic Z, Nesic N. Seizures associated with intoxication and abuse of tramadol. Clinical toxicology (Philadelphia, Pa. 2006;44(2):143-6.</ref> naloxone (given for overdose of tramadol), or any other drug which may lower the seizure threshold.
  • Increased intracranial pressure
  • Abrupt discontinuation: withdrawal may occur if tramadol is stopped without downward titration. Symptoms of withdrawal include anxiety, sweating, insomnia, pain, nausea, tremors, diarrhea, piloerection and hallucinations.

Pregnancy indications

Category C Tramadol has been shown to be embryotoxic and fetotoxic in mice, rats and rabbits. Tramadol has not been shown to be teratogenic in mice, rats and rabbits.

Breast-feeding indications

Tramadol is not indicated for breastfeeding mothers. The excretion into breast milk is 0.1% of the maternal dose.<ref name=a/>


Drug-Drug, -Food, -Herb Interactions

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Adverse Reactions/Side Effects

In a clinical trial of 550 patients with moderate pain (375 patients 65 years or older), the rates of side effects were comparable to acetaminophen with codeine, but the rate of withdrawal for side effects was greater in patients treated with tramadol.<ref name=a/> The most frequent adverse effects include constipation (38%), nausea (34%), dizziness (31%), headache (26%), somnolence (23%) and vomiting (13%).<ref name=B/>

Tramadol Adverse Reactions Chart
Incidence Body System Adverse Reactions
>10% All Dizziness (26-33%), nausea (24-40%), constipation (24-46%), headache (18-32%), somnolence (16-25%), vomiting (9-25%), dyspepsia (5-13%), pruritis (8-11%), diarrhea (5-10%), CNS stimulation (7-14%), asthenia (6-12%), sweating (6-12%)
1-10% CNS Sleep changes (1-5%), anxiety, confusion, coordination disturbances, euphoria, nervousness
Cardiovascular Vasodilation (1-5%)
Dermatologic Rash (1-5%)
GI Dry mouth (5-10%), abdominal pain (1-5%), anorexia (1-5%), flatulence (1-5%)
Genitourinary Menopausal symptoms (1-5%), urinary frequency or retention (1-5%)
Neuromuscular/skeletal Hypertonia (1-5%)
Miscellaneous Malaise (1-5%)
<1% All Accidental injury, allergic reaction, anaphylaxis, death, suicide, weight loss, serotonin syndrome, orthostatic hypotension, tachycardia, Stevens-Johnson syndrome, tremor, gait changes, amnesia, dysuria, dysgeusia, menstrual disorder, hallucinations, paresthesias

Overdosage Measures

Symptoms of overdosage include respiratory depression, lethargy, coma, seizure, or cardiac arrest.<ref name=a/>
Treatment:

  • Use general supportive measuresand maintain ventilation.
  • Naloxone reverses some, but not all symptoms and can increase the risk for seizure.
  • Convulsions can be suppressed with barbiturates or benzodiazepines.

Product Information and Distribution

Note: appearance only available for brand-name product
Dose/form Drug color(s) Drug shape Markings or odor/flavor
50 mg tablet white oblong ULTRAM/06 59
100 mg extended-release tablet white round '100' over 'ER'
200 mg extended-release tablet white round '200' over 'ER'
300 mg extended-release tablet white round '300' over 'ER'
  • Inactive ingredients for tablets: corn starch, hypromellose, lactose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, sodium glycolate, titanium dioxide, wax
  • Inactive ingredients for extended-release tablets: colloidal silicon dioxide, dibutyl sebacate, ethylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, sodium stearyl fumarate

Patient Information

  • May be taken with or without food.
  • May cause dizziness or drowsiness. Use caution when driving or operating heavy machinery.
  • DO NOT take with alcohol.
  • Extended-release tablets should be swallowed whole and not be crushed or chewed.
  • Use caution when taking tranquilizers, hypnotics, or other opiate containing analgesics
  • Contact your doctor if you are planning on becoming pregnant or think that you are pregnant
  • Do not take more often than directed, this may cause respiratory depression, seizures and death
  • Contact a health-care professional right away if: you are having difficulty breathing, have had a seizure, develop a rash, experience a change in vision, hallucinate, or have a fast heart beat.
  • Other side-effects that you may notice include constipation or diarrhea, dry mouth, and headache.

References

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PUBMED References

Efficacy Trial Articles

  1. Schnitzer TJ, Gray WL, Paster RZ, Kamin M. Efficacy of tramadol in treatment of chronic low back pain. The Journal of rheumatology. 2000 Mar;27(3):772-8.
  2. Pendeville PE, Von Montigny S, Dort JP, Veyckemans F. Double-blind randomized study of tramadol vs. paracetamol in analgesia after day-case tonsillectomy in children. European journal of anaesthesiology. 2000 Sep;17(9):576-82.
  3. Roth SH. Efficacy and safety of tramadol HCl in breakthrough musculoskeletal pain attributed to osteoarthritis. The Journal of rheumatology. 1998 Jul;25(7):1358-63.


Therapeutic Class Comparison Articles

  1. Moore RA, McQuay HJ. Single-patient data meta-analysis of 3453 postoperative patients: oral tramadol versus placebo, codeine and combination analgesics. Pain. 1997 Feb;69(3):287-94.
  2. Ng KF, Yuen TS, Ng VM. A comparison of postoperative cognitive function and pain relief with fentanyl or tramadol patient-controlled analgesia. Journal of clinical anesthesia. 2006 May;18(3):205-10.
  3. Ekman EF, Ruoff G, Kuehl K, Ralph L, Hormbrey P, Fiechtner J, et al. The COX-2 specific inhibitor Valdecoxib versus tramadol in acute ankle sprain: a multicenter randomized, controlled trial. The American journal of sports medicine. 2006 Jun;34(6):945-55.
  4. Turturro MA, Paris PM, Larkin GL. Tramadol versus hydrocodone-acetaminophen in acute musculoskeletal pain: a randomized, double-blind clinical trial. Ann Emerg Med. 1998 Aug;32(2):139-43.

Pharmacokinetics Articles

  1. Likar R, Wittels M, Molnar M, Kager I, Ziervogel G, Sittl R. Pharmacokinetic and pharmacodynamic properties of tramadol IR and SR in elderly patients: a prospective, age-group-controlled study. Clin Ther. 2006 Dec;28(12):2022-39.
  2. Murthy BP, Skee DM, Danyluk AP, Brett V, Vorsanger GJ, Moskovitz BL. Pharmacokinetic model and simulations of dose conversion from immediate- to extended-release tramadol. Current medical research and opinion. 2007 Feb;23(2):275-84.
  3. Garcia-Quetglas E, Azanza JR, Sadaba B, Munoz MJ, Gil I, Campanero MA. Pharmacokinetics of tramadol enantiomers and their respective phase I metabolites in relation to CYP2D6 phenotype. Pharmacol Res. 2007 Feb;55(2):122-30.
  4. Garrido MJ, Habre W, Rombout F, Troconiz IF. Population pharmacokinetic/pharmacodynamic modelling of the analgesic effects of tramadol in pediatrics. Pharmaceutical research. 2006 Sep;23(9):2014-23.


Drug Interaction Articles

  1. Gillman PK. Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity. British journal of anaesthesia. 2005 Oct;95(4):434-41.
  2. Mahlberg R, Kunz D, Sasse J, Kirchheiner J. Serotonin syndrome with tramadol and citalopram. The American journal of psychiatry. 2004 Jun;161(6):1129.
  3. Kesavan S, Sobala GM. Serotonin syndrome with fluoxetine plus tramadol. Journal of the Royal Society of Medicine. 1999 Sep;92(9):474-5.
  4. Dumo PA, Kielbasa LA. Successful anticoagulation and continuation of tramadol therapy in the setting of a tramadol-warfarin interaction. Pharmacotherapy. 2006 Nov;26(11):1654-7.
  5. Sabbe JR, Sims PJ, Sims MH. Tramadol-warfarin interaction. Pharmacotherapy. 1998 Jul-Aug;18(4):871-3.

Proprietary preparations

Grünenthal, which still owns the patent to tramadol, has cross-licensed the agent to pharmaceutical companies internationally. Thus, tramadol is marketed under many trade names around the world, including:

Adverse Effects Articles

Compliance Articles

Pharmacoeconomic Articles

External Links

Clinical treatment guidelines

Patient information pages

Other resources

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