Tramadol

From Wikipedia, the free encyclopedia
Tramadol
Tramadol as a racemic mixture.svg
Clinical data
Trade names Ultram, Zytram, others[2]
AHFS/Drugs.com Monograph
MedlinePlus a695011
License data
  • US FDATramadol
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
Dependence
liability
Present[1]
Routes of
administration
By mouth, IV, IM, rectal
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: Class C – Schedule 3 CD
  • US: Schedule IV
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 70% to 75% (oral), 77% (rectal), 100% (IM)[3]
Protein binding 20%[4]
Metabolism Liver-mediated demethylation and glucuronidation via CYP2D6 & CYP3A4[3][4]
Biological half-life 6.3 ± 1.4 h[4]
Excretion Urine (95%)[5]
Identifiers
CAS Number
  • 27203-92-5 YesY
PubChem CID
  • 33741
DrugBank
  • DB00193 YesY
ChemSpider
  • 31105 YesY
UNII
  • 39J1LGJ30J
KEGG
  • D08623 YesY
ChEBI
  • CHEBI:9648 N
ChEMBL
  • CHEMBL1066 YesY
ECHA InfoCard 100.043.912
Chemical and physical data
Formula C16H25NO2
Molar mass 263.381 g/mol
3D model (JSmol)
  • Interactive image
 NYesY (what is this?)  (verify)

Tramadol, sold under the brand name Ultram among others,[2] is an opioid pain medication used to treat moderate to moderately severe pain.[1] When taken by mouth in an immediate-release formulation, the onset of pain relief usually occurs within an hour.[6] It is often combined with paracetamol (acetaminophen) as this is known to improve the efficacy of tramadol in relieving pain.[3]

Serious side effects may include seizures, increased risk of serotonin syndrome, decreased alertness, and drug addiction,[1] although the risk of serotonin syndrome appears to be low.[7] Common side effects include: constipation, itchiness and nausea, among others.[1] A change in dosage may be recommended in those with kidney or liver problems.[1] It is not recommended in those who are at risk of suicide.[1] While not recommended in women who are breastfeeding, those who take it should not stop breastfeeding.[8]

It has two different mechanisms. First, it works by binding to the μ-opioid receptor.[9] Second, it acts as a serotonin–norepinephrine reuptake inhibitor (SNRI).[10][11] Tramadol is a synthetic opioid of the benzenoid class. In the body it is metabolized to desmetramadol, also known as O-desmethyltramadol, which is a more potent opioid.[12]

Tramadol was launched and marketed as "Tramal" by the German pharmaceutical company Grünenthal GmbH in 1977 in West Germany, and 20 years later it was launched in countries such as the UK, US, and Australia.[11] It is marketed under many brand names worldwide.[2]

Medical uses

Generic tramadol HCl tablets marketed by Amneal Pharmaceuticals.
Tramadol HCl for injection

Tramadol is used primarily to treat mild–severe pain, both acute and chronic.[13][14]

Its analgesic effects take about one hour to come into effect and 2 h to 4 h to peak after oral administration with an immediate-release formulation.[14][13] On a dose-by-dose basis tramadol has about one tenth the potency of morphine and is approximately equally potent when compared with pethidine and codeine.[15]

For pain moderate in severity its effectiveness is equivalent to that of morphine; for severe pain it is less effective than morphine.[13] These painkilling effects last for approximately 6 h.[14]

Available dosage forms include liquids, syrups, drops, elixirs, effervescent tablets and powders for mixing with water, capsules, tablets including extended release formulations, suppositories, compounding powder, and injections.[13]

Fibromyalgia

As of 2015 tramadol was not approved in the United States for fibromyalgia.[16] Based on three small trials with weak study design, there is fair evidence for tramadol as a second line treatment.[16]

Contraindications

Use of tramadol is not advised for people deficient in CYP2D6 enzymes.[5] The enzymes are crucial to the therapeutic effects of tramadol, by means of enabling tramadol's metabolism to desmetramadol.[13]

Pregnancy and lactation

Tramadol's use in pregnancy is generally avoided as it may cause some reversible withdrawal effects in the newborn.[17] A small prospective study in France found that, while there was an increased risk of miscarriages, there were no major malformations reported in the newborn.[17] Its use during lactation is also generally advised against, but a small trial found that infants breastfed by mothers taking tramadol were exposed to about 2.88% of the dose the mothers were taking. There was no evidence of this dose having a harmful effect on the newborn.[17]

Labour and delivery

Its use as an analgesic during labour is generally advised against due to its long-onset of action (one hour).[17] The ratio of the mean concentration of the drug in the fetus compared to that of the mother when it is given intramuscularly for labour pains has been estimated to be 94.[17]

Children

Its use in children is generally advised against, although it may be done under the supervision of a specialist.[13] On September 21, 2015 the FDA started investigating the safety of tramadol in use in persons under the age of 17. The investigation was initiated because some of these people have experienced slowed or difficult breathing.[18] The FDA lists age under 12 years old as a contraindication.[19][20]

Elderly

There is an increased risk of opioid-related adverse effects such as respiratory depression, falls, cognitive impairment and sedation.[13]

Liver and kidney failure

It is advised that the drug be used with caution in those with liver or kidney failure, due to the high dependence of the drug on the liver and kidneys for metabolism to desmetramadol and elimination, respectively.[13]

Side effects

Main side effects of tramadol. Red color denotes more serious effects, requiring immediate contact with health provider.[21]

The most common adverse effects of tramadol include nausea, dizziness, dry mouth, indigestion, abdominal pain, vertigo, vomiting, constipation, drowsiness and headache.[22][23] Compared to other opioids, respiratory depression and constipation are considered less of a problem with tramadol.[23]

There are suggestions that chronic opioid administration may induce a state of immune tolerance,[24] although tramadol, in contrast to typical opioids, may enhance immune function.[25][26][27]

Dependence and withdrawal

Long-term use of high doses of tramadol will cause physical dependence and withdrawal syndrome.[28] These include both symptoms typical of opioid withdrawal and those associated with SSRI withdrawal; symptoms include numbness, tingling, paresthesia, and tinnitus.[29] Psychiatric symptoms may include hallucinations, paranoia, extreme anxiety, panic attacks, and confusion.[30] In most cases, tramadol withdrawal will set in 12–20 hours after the last dose, but this can vary.[29] Tramadol withdrawal typically lasts longer than that of other opioids. Seven days or more of acute withdrawal symptoms can occur as opposed to typically three or four days for other codeine analogues.[29]

However, according to a 2014 report by the World Health Organizations Expert Committee on Drug Dependence '"....in many cases of tramadol dependence, a history of substance abuse is present....but....the evidence for physical dependence was considered minimal. Consequently, Tramadol is generally considered as a drug with low potential for dependence. In a recent German study (including a literature study, an analysis of two drug safety databases, and questionnaires analyses), the low abuse and low dependence potential of Tramadol were re-confirmed. The German expert group found a low prevalence of abuse or dependence in clinical practice in Germany, and concluded that Tramadol has a low potential for misuse, abuse, and dependence in Germany”.[31]

Because of the possibility of convulsions at high doses for some users, recreational use can be very dangerous.[32] Tramadol can cause a higher incidence of nausea, dizziness, loss of appetite compared with opioids, which could deter recreational use.[33] Compared to hydrocodone, fewer persons choose to use tramadol recreationally.[34]

Overdose

Fatalities with tramadol overdose have been reported and are increasing in frequency in Northern Ireland; the majority of these overdoses involve other drugs including alcohol.[35] Recognised risk factors for tramadol overdose include depression, addiction and seizures.[35] Naloxone only partially reverses the toxic effects of tramadol overdose and may increase the risk of seizures.[13]

Interactions

Tramadol may interact with serotonergics, monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, noradrenergic and specific serotonergic antidepressants, serotonin antagonists and reuptake inhibitors, other opioid analgesics (pethidine (meperidine), tapentadol, oxycodone, and fentanyl), dextromethorphan, certain migraine medications (triptans, ergots), certain anxiolytics (such as the SSRIs and buspirone), certain antibiotics (namely, linezolid and isoniazid), certain herbs (e.g. St. John's wort, passiflora, etc.), amphetamines, substituted amphetamines, phenethylamine and substituted phenethylamines, phentermine, lithium, methylene blue as well as numerous other therapeutic agents.[5][13] As it is a substrate of CYP3A4 and CYP2D6, any agents with the ability to inhibit or induce these enzymes will likely interact with tramadol. A pressor response similar to the so-called "cheese effect" was noted in combinations of amphetamine and tramadol, which appears to cause dysfunction of or toxicity to epinephrine/norepinephrine receptors.[13][23] Cyclobenzaprine, a commonly-used muscle relaxant, atypical analgesic adjunct, as well as a potentiator often used with analgesics like codeine, dihydrocodeine, hydrocodone and the like, is structurally related to the tricyclic antidepressants [36] and therefore should not be used with tramadol; this is also the case for trazodone[37]

Pharmacology

Mechanism of action

Tramadol (and metabolite)[38][39][40]
Site Tramadol DSMT Species Ref
MOR 1,600–12,486
2,120–8,300
≥1,000 (EC50)
5.4–18.6
17 ((+))
≥240 (EC50)
Human
Rat
Human
[41][42][43]
[44][45]
[46][12]
DOR >10,000
57,600–100,000
≥2,900
690 (+))
Human
Rat
[41][42][47]
[45][44]
KOR >10,000
42,700–81,000
≥450
1,800 (+))
Human
Rat
[41][42][47]
[45][44]
SERT ~900 (IC50)
992–1,190
>20,000 (IC50)
2,980 ((−)) (IC50)
Human
Rat
[48]
[45][12]
NET 14,600
785
1,080 (−) (IC50)
>860 (IC50)
Human
Rat
[12]
[45][12]
DAT >100,000 >20,000 Rat [49][47]
5-HT1A >20,000 >20,000 Rat [47]
5-HT2A >20,000 >20,000 Rat [47]
5-HT2C 1,000 (IC50) 1,300 (IC50) Rat [50][51]
5-HT3 >20,000 >20,000 Rat [47]
NK1 IA  ? Rat [52][53]
M1 >20,000
3,400 (IC50)
>20,000
2,000 (IC50)
Rat
Multiple
[47]
[54][55]
M2 ND ND ND ND
M3 1,000 (IC50) IA Human [55][56]
M4 ND ND ND ND
M5 ND ND ND ND
α7 7,400 ND Chicken [57]
σ1 >10,000 ND Rat [38][58]
σ2 >10,000 ND Rat [38]
NMDAR 16,400 (IC50) 16,500 (IC50) Human [59]
NMDAR
(MK-801)
>20,000 >20,000 Rat [47]
GABAA >100,000 (IC50) >100,000 (IC50) Human [59]
GlyR >100,000 (IC50) >100,000 (IC50) Human [59]
TRPA1 100–
10,000 (SI)
1,000–
10,000 (SI)
Human [60]
TRPV1 >10,000 (IC50) >10,000 (IC50) Human [60][61]
Values are Ki (nM), unless otherwise noted. The smaller the value, the more strongly the drug binds to the site.

Tramadol and monoamine reuptake and release[62]
Action Value
5-HT reuptake 1,820
5-HT release >10,000
NE reuptake 2,770
NE release >10,000
DA reuptake >10,000
DA release >10,000
Values for reuptake inhibition are Ki (nM) and for release induction are EC50 (nM).

Tramadol has been found to possess the following actions:[39][40][63]

Tramadol acts on the opioid receptors through its major active metabolite desmetramadol, which has as much as 700-fold higher affinity for the MOR relative to tramadol.[12] Moreover, tramadol itself has been found to possess no efficacy in activating the MOR in functional activity assays, whereas desmetramadol activates the receptor with high intrinsic activity (Emax equal to that of morphine).[46][12][64] As such, desmetramadol is exclusively responsible for the opioid effects of tramadol.[65] Both tramadol and desmetramadol have pronounced selectivity for the MOR over the DOR and KOR in terms of binding affinity.[47][42][44]

Tramadol is well-established as a serotonin reuptake inhibitor.[39][40] In addition, a few studies have found that it also acts as a serotonin releasing agent (1–10 μM), similar in effect to fenfluramine.[66][67][68][69] The serotonin releasing effects of tramadol could be blocked by sufficiently high concentrations of the serotonin reuptake inhibitor 6-nitroquipazine, which is in accordance with other serotonin releasing agents like fenfluramine and MDMA.[66][68][69] However, two more recent studies failed to find a releasing effect of tramadol at respective concentrations up to 10 and 30 μM.[70][69][62] In addition to serotonergic activity, tramadol is also a norepinephrine reuptake inhibitor.[39][40] It is not a norepinephrine releasing agent.[71][72][73][62] Tramadol does not inhibit the reuptake or induce the release of dopamine.[71][62]

A positron emission tomography imaging study found that single oral 50 mg and 100 mg doses of tramadol to human volunteers resulted in 34.7% and 50.2% respective mean occupation of the serotonin transporter (SERT) in the thalamus.[74] The estimated median effective dose (ED50) for SERT occupancy hence was 98.1 mg, which was associated with a plasma tramadol level of about 330 ng/mL (1,300 nM).[74] It was also estimated that the maximum daily dosage of tramadol of 400 mg (100 mg q.i.d.) would result in as much as 78.7% occupancy of the SERT (in association with a plasma concentration of 1,220 ng/mL or 4,632 nM).[74] This is close to that of selective serotonin reuptake inhibitors (SSRIs), which occupy the SERT by 80% or more.[74]

Peak plasma concentrations during treatment with clinical dosages of tramadol have generally been found to be in the range of 70 to 592 ng/mL (266–2,250 nM) for tramadol and 55 to 143 ng/mL (221–573 nM) for desmetramadol.[75] The highest levels of tramadol were observed with the maximum oral daily dosage of 400 mg per day divided into one 100 mg dose every 6 hours (i.e., four 100 mg doses evenly spaced out per day).[75][76] There is some accumulation of tramadol with chronic administration; peak plasma levels of tramadol with the maximum oral daily dosage (100 mg q.i.d.) are about 16% higher and the area-under-the-curve levels 36% higher than following a single oral 100 mg dose.[75] Positron emission tomography imaging studies have reportedly found that tramadol levels are at least 4-fold higher in the brain than in plasma.[71][77] Conversely, brain levels of desmetramadol "only slowly approach those in plasma".[71] The plasma protein binding of tramadol is only 4 to 20%; hence, almost all tramadol in circulation is free and thus bioactive.[78][79][80]

Correspondence to clinical effects

Co-administration of quinidine, a potent CYP2D6 inhibitor, with tramadol, a combination which results in markedly reduced levels of desmetramadol, was found not to significantly affect the analgesic effects of tramadol in human volunteers.[12][79] However, other studies have found that the analgesic effects of tramadol are significantly decreased or even absent in CYP2D6 poor metabolizers.[12][65] The analgesic effects of tramadol are only partially reversed by naloxone in human volunteers,[12] hence indicating that its opioid action is unlikely the sole factor; tramadol's analgesic effects are also partially reversed by α2-adrenergic receptor antagonists like yohimbine, the 5-HT3 receptor antagonist ondansetron, and the 5-HT7 receptor antagonists SB-269970 and SB-258719.[14][81] Pharmacologically, tramadol is similar to tapentadol and methadone in that it not only binds to the MOR, but also inhibits the reuptake of serotonin and norepinephrine[3] due to its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity.[82]

Tramadol has inhibitory actions on the 5-HT2C receptor. Antagonism of 5-HT2C could be partially responsible for tramadol's reducing effect on depressive and obsessive–compulsive symptoms in patients with pain and co-morbid neurological illnesses.[50] 5-HT2C blockade may also account for its lowering of the seizure threshold, as 5-HT2C knockout mice display significantly increased vulnerability to epileptic seizures, sometimes resulting in spontaneous death. However, the reduction of seizure threshold could be attributed to tramadol's putative inhibition of GABAA receptors at high doses (significant inhibition at 100 μM).[59][63] In addition, desmetramadol is a high-affinity ligand of the DOR, and activation of this receptor could be involved in tramadol's ability to provoke seizures in some individuals, as DOR agonists are well-known for inducing seizures.[44]

Nausea and vomiting caused by tramadol is thought to be due to activation of the 5-HT3 receptor via increased serotonin levels.[48] In accordance, the 5-HT3 receptor antagonist metoclopramide can be used to treat tramadol-associated nausea and vomiting.[48] Tramadol and desmetramadol themselves do not bind to the 5-HT3 receptor.[48][40]

Pharmacokinetics

Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2B6, CYP2D6 and CYP3A4, being O- and N-demethylated to five different metabolites. Of these, desmetramadol (O-desmethyltramadol) is the most significant since it has 200 times the μ-affinity of (+)-tramadol, and furthermore has an elimination half-life of nine hours, compared with six hours for tramadol itself. As with codeine, in the 6% of the population that have reduced CYP2D6 activity (hence reducing metabolism), there is therefore a reduced analgesic effect. Those with decreased CYP2D6 activity require a dose increase of 30% in order to achieve the same degree of pain relief as those with a normal level of CYP2D6 activity.[83][84]

Phase II hepatic metabolism renders the metabolites water-soluble, which are excreted by the kidneys. Thus, reduced doses may be used in renal and hepatic impairment.[14]

Its volume of distribution is approximately 306 L after oral administration and 203 L after parenteral administration.[14]

Chemistry

Tramadol is marketed as a racemic mixture of both R- and S-stereoisomers.[3] This is because the two isomers complement each other's analgesic activity.[3] The (+)-isomer is predominantly active as an opiate with a higher affinity for the µ-opiate receptor (20 times higher affinity than the (-)-isomer).[85]

Synthesis and stereoisomerism

(1R,2R)-Tramadol (1S,2S)-Tramadol
(1R,2R)-tramadol (1S,2S)-tramadol
(1R,2S)-Tramadol (1S,2R)-Tramadol
(1R,2S)-tramadol (1S,2R)-tramadol

The chemical synthesis of tramadol is described in the literature.[86] Tramadol [2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol] has two stereogenic centers at the cyclohexane ring. Thus, 2-(dimethylaminomethyl)-1-(3-methoxyphenyl)cyclohexanol may exist in four different configurational forms:

  • (1R,2R)-isomer
  • (1S,2S)-isomer
  • (1R,2S)-isomer
  • (1S,2R)-isomer

The synthetic pathway leads to the racemate (1:1 mixture) of (1R,2R)-isomer and the (1S,2S)-isomer as the main products. Minor amounts of the racemic mixture of the (1R,2S)-isomer and the (1S,2R)-isomer are formed as well. The isolation of the (1R,2R)-isomer and the (1S,2S)-isomer from the diastereomeric minor racemate [(1R,2S)-isomer and (1S,2R)-isomer] is realized by the recrystallization of the hydrochlorides. The drug tramadol is a racemate of the hydrochlorides of the (1R,2R)-(+)- and the (1S,2S)-(−)-enantiomers. The resolution of the racemate [(1R,2R)-(+)-isomer / (1S,2S)-(−)-isomer] was described[87] employing (R)-(−)- or (S)-(+)-mandelic acid. This process does not find industrial application, since tramadol is used as a racemate, despite known different physiological effects[88] of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals[89] and in humans.[90]

Detection in biological fluids

Tramadol and desmetramadol may be quantified in blood, plasma or serum to monitor for abuse, confirm a diagnosis of poisoning or assist in the forensic investigation of a sudden death. Most commercial opiate immunoassay screening tests do not cross-react significantly with tramadol or its major metabolites, so chromatographic techniques must be used to detect and quantitate these substances. The concentration of desmetramadol in the blood or plasma of a person who has taken tramadol is generally 10–20% those of the parent drug.[91][92][93]

History

The U.S. Food and Drug Administration (FDA) approved tramadol in March 1995 and an extended-release (ER) formulation in September 2005.[94] Tramadol is protected by US patents nos. 6,254,887[95] and 7,074,430.[96][97] The FDA listed the patents' expiration as 10 May 2014.[96] However, in August 2009, US District Court for the District of Delaware ruled the patents invalid, which, if it survives appeal, would permit manufacture and distribution of generic equivalents of Ultram ER in the United States.[98]

Society and culture

Legal status

Effective August 18, 2014, tramadol has been placed into Schedule IV of the federal Controlled Substances Act in the United States.[99][100] In addition, many states, including Arkansas, Georgia, Kentucky, Illinois, Mississippi, New York, North Dakota, Ohio, Oklahoma, South Carolina, Tennessee, West Virginia, Wyoming and the U.S. military[citation needed] have already classified tramadol as a Schedule IV controlled substance under state law.[101][102][103]

Tramadol is classified in Schedule 4 (prescription only) in Australia, rather than as a Schedule 8 Controlled Drug (Possession without authority illegal) like most other opioids.[13]

Effective May 2008, Sweden classified tramadol as a controlled substance in the same category as codeine and dextropropoxyphene, but allows a normal prescription be used currently.[104]

The UK classified tramadol as a Schedule 3 controlled drug (CD) on 10 June 2014, but exempted it from the safe custody requirement.[105]

Research

Investigational uses

False findings about sources in nature

In 2013, researchers reported that tramadol was found in relatively high concentrations (1%+) in the roots of the African pin cushion tree (Nauclea latifolia).[114] In 2014, however, it was reported that the presence of tramadol in the tree roots was the result of tramadol having been administered to cattle by farmers in the region:[115] tramadol and its metabolites were present in the animals' excreta, which contaminated the soil around the trees. Therefore, tramadol and its mammalian metabolites were found in tree roots in the far north of Cameroon, but not in the south where it is not administered to farm animals.[115]

A 2014 editorial in Lab Times online contested the notion that tramadol in tree roots was the result of anthropogenic contamination, stating that samples were taken from trees which grew in national parks, where livestock were forbidden; it also quoted researcher Michel de Waard, who stated that "thousands and thousands of tramadol-treated cattle sitting around a single tree and urinating there" would be required to produce the concentrations discovered.[116]

In 2015, radiocarbon analysis confirmed that the tramadol found in N.latifolia roots could not be plant-derived and was of synthetic origin.[117]

Veterinary medicine

Tramadol may be used to treat post-operative, injury-related, and chronic (e.g., cancer-related) pain in dogs and cats as well as rabbits, coatis, many small mammals including rats and flying squirrels, guinea pigs, ferrets, and raccoons.[118]

Pharmacokinetics of tramadol across the species[118]
Species Half-life (h) for parent drug Half-life (h) for desmetramadol Maximum plasma concentration (ng/mL) for parent drug Maximum plasma concentration (ng/mL) for desmetramadol
Camel 3.2 (IM), 1.3 (IV) 0.44 (IV)
Cat 3.40 (oral), 2.23 (IV) 4.82 (oral), 4.35 (IV) 914 (oral), 1323 (IV) 655 (oral), 366 (IV)
Dog 1.71 (oral), 1.80 (IV), 2.24 (rectal) 2.18 (oral), 90-5000 (IV) 1402.75 (oral) 449.13 (oral), 90–350 (IV)
Donkey 4.2 (oral), 1.5 (IV) 2817 (oral)
Goat 2.67 (oral), 0.94 (IV) 542.9 (oral)
Horses 1.29–1.53 (IV), 10.1 (oral) 4 (oral) 637 (IV), 256 (oral) 47 (oral)
Llama 2.54 (IM), 2.12 (IV) 7.73 (IM), 10.4 (IV) 4036 (IV), 1360 (IM) 158 (IV), 158 (IM)

See also

References

  1. ^ a b c d e f "Tramadol Hydrochloride". The American Society of Health-System Pharmacists. Retrieved Dec 1, 2014. 
  2. ^ a b c Drugs.com International names for tramadol Page accessed April 23, 2016
  3. ^ a b c d e f Brayfield, A, ed. (13 December 2013). "Tramadol Hydrochloride". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 5 April 2014. 
  4. ^ a b c "Ultram, Ultram ER (tramadol) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 28 November 2013. 
  5. ^ a b c "Australian Label: Tramadol Sandoz 50 mg capsules" (PDF). TGA eBusiness Services. 4 November 2011. Retrieved 6 April 2014. 
  6. ^ Katz WA (1996). "Pharmacology and clinical experience with tramadol in osteoarthritis". Drugs. 52 Suppl 3: 39–47. doi:10.2165/00003495-199600523-00007. PMID 8911798. 
  7. ^ Nicole M. Ryan; Geoffrey K. Isbister (April 2015). "Tramadol overdose causes seizures and respiratory depression but serotonin toxicity appears unlikely". Clinical Toxicology. 53 (6): 545–50. doi:10.3109/15563650.2015.1036279. PMID 25901965. 
  8. ^ "Tramadol Pregnancy and Breastfeeding Warnings". Drugs.com. Retrieved 5 September 2016. 
  9. ^ Hennies HH, Friderichs E, Schneider J (July 1988). "Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids". Arzneimittel-Forschung. 38 (7): 877–80. PMID 2849950. 
  10. ^ Now What? DEA Tosses Tramadol in Schedule IV, By Nadia Awad, MedPage Today, Jul. 10, 2014
  11. ^ a b Leppert, W (November–December 2009). "Tramadol as an analgesic for mild to moderate cancer pain" (PDF). Pharmacological reports. 61 (6): 978–92. doi:10.1016/s1734-1140(09)70159-8. PMID 20081232. 
  12. ^ a b c d e f g h i j Raffa RB, Buschmann H, Christoph T, Eichenbaum G, Englberger W, Flores CM, Hertrampf T, Kögel B, Schiene K, Straßburger W, Terlinden R, Tzschentke TM (2012). "Mechanistic and functional differentiation of tapentadol and tramadol". Expert Opin Pharmacother. 13 (10): 1437–49. doi:10.1517/14656566.2012.696097. PMID 22698264. 
  13. ^ a b c d e f g h i j k l Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3. 
  14. ^ a b c d e f Grond S, Sablotzki A (2004). "Clinical pharmacology of tramadol". Clinical Pharmacokinetics. 43 (13): 879–923. doi:10.2165/00003088-200443130-00004. PMID 15509185. 
  15. ^ Lee CR, McTavish D, Sorkin EM (1993). "Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states". Drugs. 46 (2): 313–40. doi:10.2165/00003495-199346020-00008. PMID 7691519. 
  16. ^ a b MacLean, AJ; Schwartz, TL (May 2015). "Tramadol for the treatment of fibromyalgia". Expert Review of Neurotherapeutics. 15 (5): 469–75. doi:10.1586/14737175.2015.1034693. PMID 25896486. 
  17. ^ a b c d e Bloor M, Paech MJ, Kaye R (2012). "Tramadol in pregnancy and lactation". International Journal of Obstetric Anesthesia. 21 (2): 163–67. doi:10.1016/j.ijoa.2011.10.008. PMID 22317891. 
  18. ^ "FDA Drug Safety Communication: FDA evaluating the risks of using the pain medicine tramadol in children aged 17 and younger". FDA. FDA Drug Safety and Availability. Retrieved 21 September 2015. 
  19. ^ Commissioner, Office of the. "Press Announcements - FDA statement from Douglas Throckmorton, M.D., deputy center director for regulatory programs, Center for Drug Evaluation and Research, on new warnings about the use of codeine and tramadol in children & nursing mothers". www.fda.gov. Retrieved 21 April 2017. 
  20. ^ "FDA Drug Safety Communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women". Food and Drug Administration. 
  21. ^ "Tramadol". MedlinePlus. American Society of Health-System Pharmacists. 1 September 2008. Retrieved 29 September 2009. 
  22. ^ Langley PC, Patkar AD, Boswell KA, Benson CJ, Schein JR (2010). "Adverse event profile of tramadol in recent clinical studies of chronic osteoarthritis pain". Current Medical Research and Opinion. 26 (1): 239–51. doi:10.1185/03007990903426787. PMID 19929615. 
  23. ^ a b c Keating GM (2006). "Tramadol sustained-release capsules". Drugs. 66 (2): 223–30. doi:10.2165/00003495-200666020-00006. PMID 16451094. 
  24. ^ Bryant et al. 1988 and Rouveix 1992 cited by Collett BJ (July 2001). "Chronic opioid therapy for non-cancer pain". British Journal of Anaesthesia. 87 (1): 133–43. doi:10.1093/bja/87.1.133. PMID 11460802. 
  25. ^ Sacerdote P, Bianchi M, Gaspani L, Manfredi B, Maucione A, Terno G, Ammatuna M, Panerai AE (2000). "The effects of tramadol and morphine on immune responses and pain after surgery in cancer patients". Anesthesia & Analgesia. 90 (6): 1411–14. doi:10.1097/00000539-200006000-00028. PMID 10825330. 
  26. ^ Liu Z, Gao F, Tian Y (2006). "Effects of morphine, fentanyl and tramadol on human immune response". J. Huazhong Univ. Sci. Technol. Med. Sci. 26 (4): 478–81. doi:10.1007/s11596-006-0427-5. PMID 17120754. 
  27. ^ Sacerdote P, Bianchi M, Manfredi B, Panerai AE (1997). "Effects of tramadol on immune responses and nociceptive thresholds in mice". Pain. 72 (3): 325–30. doi:10.1016/S0304-3959(97)00055-9. PMID 9313273. 
  28. ^ "Withdrawal syndrome and dependence: tramadol too". Prescrire Int. 12 (65): 99–100. 2003. PMID 12825576. 
  29. ^ a b c Epstein DH, Preston KL, Jasinski DR (2006). "Abuse liability, behavioral pharmacology, and physical-dependence potential of opioids in humans and laboratory animals: lessons from tramadol". Biological Psychology. 73 (1): 90–99. doi:10.1016/j.biopsycho.2006.01.010. PMC 2943845Freely accessible. PMID 16497429. 
  30. ^ Senay EC, Adams EH, Geller A, Inciardi JA, Muñoz A, Schnoll SH, Woody GE, Cicero TJ (April 2003). "Physical dependence on Ultram (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur". Drug Alcohol Depend. 69 (3): 233–41. doi:10.1016/S0376-8716(02)00321-6. PMID 12633909. 
  31. ^ Tramadol - Update Review Report. WHO (16‐20 June 2014)
  32. ^ Jovanović-Cupić V, Martinović Z, Nesić N (2006). "Seizures associated with intoxication and abuse of tramadol". Clinical Toxicology. 44 (2): 143–46. doi:10.1080/1556365050014418. PMID 16615669. 
  33. ^ Rodriguez RF, Bravo LE, Castro F, Montoya O, Castillo JM, Castillo MP, Daza P, Restrepo JM, Rodriguez MF (2007). "Incidence of weak opioids adverse events in the management of cancer pain: a double-blind comparative trial". Journal of Palliative Medicine. 10 (1): 56–60. doi:10.1089/jpm.2006.0117. PMID 17298254. 
  34. ^ Adams EH, Breiner S, Cicero TJ, Geller A, Inciardi JA, Schnoll SH, Senay EC, Woody GE (2006). "A comparison of the abuse liability of tramadol, NSAIDs, and hydrocodone in patients with chronic pain". Journal of Pain and Symptom Management. 31 (5): 465–76. doi:10.1016/j.jpainsymman.2005.10.006. PMID 16716877. 
  35. ^ a b Randall C, Crane J (2014). "Tramadol deaths in Northern Ireland: a review of cases from 1996 to 2012". Journal of Forensic and Legal Medicine. 23: 32–36. doi:10.1016/j.jflm.2014.01.006. PMID 24661703. 
  36. ^ "cyclobenzaprine oral : Uses, Side Effects, Interactions, Pictures, Warnings & Dosing". WebMD. Retrieved 2016-11-08. 
  37. ^ "Trazodone: Common sleep drug is little-known antidepressant". Consumer Reports. Retrieved 2016-11-08. 
  38. ^ a b c Roth, BL; Driscol, J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017. 
  39. ^ a b c d Minami K, Uezono Y, Ueta Y (2007). "Pharmacological aspects of the effects of tramadol on G-protein coupled receptors". J. Pharmacol. Sci. 103 (3): 253–60. PMID 17380034. 
  40. ^ a b c d e Minami K, Ogata J, Uezono Y (2015). "What is the main mechanism of tramadol?". Naunyn Schmiedebergs Arch. Pharmacol. 388 (10): 999–1007. doi:10.1007/s00210-015-1167-5. PMID 26292636. 
  41. ^ a b c Wentland MP, Lou R, Lu Q, Bu Y, VanAlstine MA, Cohen DJ, Bidlack JM (2009). "Syntheses and opioid receptor binding properties of carboxamido-substituted opioids". Bioorg. Med. Chem. Lett. 19 (1): 203–8. doi:10.1016/j.bmcl.2008.10.134. PMID 19027293. 
  42. ^ a b c d Shen Q, Qian Y, Huang X, Xu X, Li W, Liu J, Fu W (2016). "Discovery of Potent and Selective Agonists of δ Opioid Receptor by Revisiting the "Message-Address" Concept". ACS Med Chem Lett. 7 (4): 391–6. doi:10.1021/acsmedchemlett.5b00423. PMC 4834657Freely accessible. PMID 27096047. 
  43. ^ Volpe DA, McMahon Tobin GA, Mellon RD, Katki AG, Parker RJ, Colatsky T, Kropp TJ, Verbois SL (2011). "Uniform assessment and ranking of opioid μ receptor binding constants for selected opioid drugs". Regul. Toxicol. Pharmacol. 59 (3): 385–90. doi:10.1016/j.yrtph.2010.12.007. PMID 21215785. 
  44. ^ a b c d e Potschka H, Friderichs E, Löscher W (September 2000). "Anticonvulsant and proconvulsant effects of tramadol, its enantiomers and its M1 metabolite in the rat kindling model of epilepsy". Br. J. Pharmacol. 131 (2): 203–12. doi:10.1038/sj.bjp.0703562. PMC 1572317Freely accessible. PMID 10991912. 
  45. ^ a b c d e Codd EE, Shank RP, Schupsky JJ, Raffa RB (1995). "Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception". J. Pharmacol. Exp. Ther. 274 (3): 1263–70. PMID 7562497. 
  46. ^ a b Gillen C, Haurand M, Kobelt DJ, Wnendt S (2000). "Affinity, potency and efficacy of tramadol and its metabolites at the cloned human mu-opioid receptor". Naunyn Schmiedebergs Arch. Pharmacol. 362 (2): 116–21. PMID 10961373. 
  47. ^ a b c d e f g h i Frink MC, Hennies HH, Englberger W, Haurand M, Wilffert B (1996). "Influence of tramadol on neurotransmitter systems of the rat brain". Arzneimittelforschung. 46 (11): 1029–36. PMID 8955860. 
  48. ^ a b c d Barann M, Urban B, Stamer U, Dorner Z, Bönisch H, Brüss M (2006). "Effects of tramadol and O-demethyl-tramadol on human 5-HT reuptake carriers and human 5-HT3A receptors: a possible mechanism for tramadol-induced early emesis". Eur. J. Pharmacol. 531 (1-3): 54–8. doi:10.1016/j.ejphar.2005.11.054. PMID 16427041. 
  49. ^ Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL (1992). "Opioid and nonopioid components independently contribute to the mechanism of action of tramadol, an 'atypical' opioid analgesic". J. Pharmacol. Exp. Ther. 260 (1): 275–85. PMID 1309873. 
  50. ^ a b Ogata J, Minami K, Uezono Y, Okamoto T, Shiraishi M, Shigematsu A, Ueta Y (2004). "The inhibitory effects of tramadol on 5-hydroxytryptamine type 2C receptors expressed in Xenopus oocytes". Anesth. Analg. 98 (5): 1401–6, table of contents. PMID 15105221. 
  51. ^ Horishita T, Minami K, Uezono Y, Shiraishi M, Ogata J, Okamoto T, Shigematsu A (2006). "The tramadol metabolite, O-desmethyl tramadol, inhibits 5-hydroxytryptamine type 2C receptors expressed in Xenopus Oocytes". Pharmacology. 77 (2): 93–9. doi:10.1159/000093179. PMID 16679816. 
  52. ^ Okamoto T, Minami K, Uezono Y, Ogata J, Shiraishi M, Shigematsu A, Ueta Y (2003). "The inhibitory effects of ketamine and pentobarbital on substance p receptors expressed in Xenopus oocytes". Anesth. Analg. 97 (1): 104–10, table of contents. PMID 12818951. 
  53. ^ Minami K, Yokoyama T, Ogata J, Uezono Y (2011). "The tramadol metabolite O-desmethyl tramadol inhibits substance P-receptor functions expressed in Xenopus oocytes". J. Pharmacol. Sci. 115 (3): 421–4. PMID 21372504. 
  54. ^ Shiraishi M, Minami K, Uezono Y, Yanagihara N, Shigematsu A (2001). "Inhibition by tramadol of muscarinic receptor-induced responses in cultured adrenal medullary cells and in Xenopus laevis oocytes expressing cloned M1 receptors". J. Pharmacol. Exp. Ther. 299 (1): 255–60. PMID 11561087. 
  55. ^ a b Nakamura M, Minami K, Uezono Y, Horishita T, Ogata J, Shiraishi M, Okamoto T, Terada T, Sata T (2005). "The effects of the tramadol metabolite O-desmethyl tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M1 or M3 receptors". Anesth. Analg. 101 (1): 180–6, table of contents. doi:10.1213/01.ANE.0000154303.93909.A3. PMID 15976229. 
  56. ^ Shiga Y, Minami K, Shiraishi M, Uezono Y, Murasaki O, Kaibara M, Shigematsu A (2002). "The inhibitory effects of tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M(3) receptors". Anesth. Analg. 95 (5): 1269–73, table of contents. PMID 12401609. 
  57. ^ Shiraishi M, Minami K, Uezono Y, Yanagihara N, Shigematsu A, Shibuya I (2002). "Inhibitory effects of tramadol on nicotinic acetylcholine receptors in adrenal chromaffin cells and in Xenopus oocytes expressing alpha 7 receptors". Br. J. Pharmacol. 136 (2): 207–16. doi:10.1038/sj.bjp.0704703. PMC 1573343Freely accessible. PMID 12010769. 
  58. ^ Sánchez-Fernández C, Montilla-García Á, González-Cano R, Nieto FR, Romero L, Artacho-Cordón A, Montes R, Fernández-Pastor B, Merlos M, Baeyens JM, Entrena JM, Cobos EJ (2014). "Modulation of peripheral μ-opioid analgesia by σ1 receptors". J. Pharmacol. Exp. Ther. 348 (1): 32–45. doi:10.1124/jpet.113.208272. PMID 24155346. 
  59. ^ a b c d Hara K, Minami K, Sata T (2005). "The effects of tramadol and its metabolite on glycine, gamma-aminobutyric acidA, and N-methyl-D-aspartate receptors expressed in Xenopus oocytes". Anesth. Analg. 100 (5): 1400–5, table of contents. doi:10.1213/01.ANE.0000150961.24747.98. PMID 15845694. 
  60. ^ a b Miyano K, Minami K, Yokoyama T, Ohbuchi K, Yamaguchi T, Murakami S, Shiraishi S, Yamamoto M, Matoba M, Uezono Y (2015). "Tramadol and its metabolite m1 selectively suppress transient receptor potential ankyrin 1 activity, but not transient receptor potential vanilloid 1 activity". Anesth. Analg. 120 (4): 790–8. doi:10.1213/ANE.0000000000000625. PMID 25642661. 
  61. ^ Marincsák R, Tóth BI, Czifra G, Szabó T, Kovács L, Bíró T (2008). "The analgesic drug, tramadol, acts as an agonist of the transient receptor potential vanilloid-1". Anesth. Analg. 106 (6): 1890–6. doi:10.1213/ane.0b013e318172fefc. PMID 18499628. 
  62. ^ a b c d Rothman RB, Baumann MH (2006). "Therapeutic potential of monoamine transporter substrates". Curr Top Med Chem. 6 (17): 1845–59. PMID 17017961. 
  63. ^ a b Vazzana M, Andreani T, Fangueiro J, Faggio C, Silva C, Santini A, Garcia ML, Silva AM, Souto EB (2015). "Tramadol hydrochloride: pharmacokinetics, pharmacodynamics, adverse side effects, co-administration of drugs and new drug delivery systems". Biomed. Pharmacother. 70: 234–8. doi:10.1016/j.biopha.2015.01.022. PMID 25776506. 
  64. ^ Minami K, Sudo Y, Miyano K, Murphy RS, Uezono Y (2015). "µ-Opioid receptor activation by tramadol and O-desmethyltramadol (M1)". J Anesth. 29 (3): 475–479. doi:10.1007/s00540-014-1946-z. PMID 25394761. 
  65. ^ a b Coller JK, Christrup LL, Somogyi AA (2009). "Role of active metabolites in the use of opioids". Eur. J. Clin. Pharmacol. 65 (2): 121–39. doi:10.1007/s00228-008-0570-y. PMID 18958460. 
  66. ^ a b Driessen B, Reimann W (January 1992). "Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro". British Journal of Pharmacology. 105 (1): 147–51. doi:10.1111/j.1476-5381.1992.tb14226.x. PMC 1908625Freely accessible. PMID 1596676. 
  67. ^ Bamigbade TA, Davidson C, Langford RM, Stamford JA (September 1997). "Actions of tramadol, its enantiomers and principal metabolite, O-desmethyltramadol, on serotonin (5-HT) efflux and uptake in the rat dorsal raphe nucleus". British Journal of Anaesthesia. 79 (3): 352–56. doi:10.1093/bja/79.3.352. PMID 9389855. 
  68. ^ a b Reimann W, Schneider F (May 1998). "Induction of 5-hydroxytryptamine release by tramadol, fenfluramine and reserpine". European Journal of Pharmacology. 349 (2–3): 199–203. doi:10.1016/S0014-2999(98)00195-2. PMID 9671098. 
  69. ^ a b c Gobbi M, Moia M, Pirona L, Ceglia I, Reyes-Parada M, Scorza C, Mennini T (September 2002). "p-Methylthioamphetamine and 1-(m-chlorophenyl)piperazine, two non-neurotoxic 5-HT releasers in vivo, differ from neurotoxic amphetamine derivatives in their mode of action at 5-HT nerve endings in vitro". Journal of Neurochemistry. 82 (6): 1435–43. doi:10.1046/j.1471-4159.2002.01073.x. PMID 12354291. 
  70. ^ Gobbi M, Mennini T (1999). "Release studies with rat brain cortical synaptosomes indicate that tramadol is a 5-hydroxytryptamine uptake blocker and not a 5-hydroxytryptamine releaser". Eur. J. Pharmacol. 370 (1): 23–6. PMID 10323276. 
  71. ^ a b c d Driessen B, Reimann W, Giertz H (1993). "Effects of the central analgesic tramadol on the uptake and release of noradrenaline and dopamine in vitro". Br. J. Pharmacol. 108 (3): 806–11. PMC 1908052Freely accessible. PMID 8467366. 
  72. ^ Reimann W, Hennies HH (1994). "Inhibition of spinal noradrenaline uptake in rats by the centrally acting analgesic tramadol". Biochem. Pharmacol. 47 (12): 2289–93. PMID 8031323. 
  73. ^ Halfpenny DM, Callado LF, Hopwood SE, Bamigbade TA, Langford RM, Stamford JA (1999). "Effects of tramadol stereoisomers on norepinephrine efflux and uptake in the rat locus coeruleus measured by real time voltammetry". Br J Anaesth. 83 (6): 909–15. PMID 10700792. 
  74. ^ a b c d Ogawa K, Tateno A, Arakawa R, Sakayori T, Ikeda Y, Suzuki H, Okubo Y (2014). "Occupancy of serotonin transporter by tramadol: a positron emission tomography study with [11C]DASB". Int. J. Neuropsychopharmacol. 17 (6): 845–50. doi:10.1017/S1461145713001764. PMID 24423243. 
  75. ^ a b c Grond S, Sablotzki A (2004). "Clinical pharmacology of tramadol". Clin Pharmacokinet. 43 (13): 879–923. PMID 15509185. 
  76. ^ https://www.drugs.com/dosage/tramadol.html
  77. ^ Tao Q, Stone DJ, Borenstein MR, Codd EE, Coogan TP, Desai-Krieger D, Liao S, Raffa RB (2002). "Differential tramadol and O-desmethyl metabolite levels in brain vs. plasma of mice and rats administered tramadol hydrochloride orally". J Clin Pharm Ther. 27 (2): 99–106. PMID 11975693. 
  78. ^ Gibson TP (1996). "Pharmacokinetics, efficacy, and safety of analgesia with a focus on tramadol HCl". Am. J. Med. 101 (1A): 47S–53S. PMID 8764760. 
  79. ^ a b Dayer P, Collart L, Desmeules J (1994). "The pharmacology of tramadol". Drugs. 47 Suppl 1: 3–7. PMID 7517823. 
  80. ^ Nobilis, M; Kopecký, J; Květina, J; Chládek, J; Svoboda, Z; Vořı́šek, V; Perlı́k, F; Pour, M; Kuneš, J (2002). "High-performance liquid chromatographic determination of tramadol and its O-desmethylated metabolite in blood plasma". Journal of Chromatography A. 949 (1-2): 11–22. doi:10.1016/S0021-9673(01)01567-9. ISSN 0021-9673. 
  81. ^ Yanarates O, Dogrul A, Yildirim V, Sahin A, Sizlan A, Seyrek M, Akgül O, Kozak O, Kurt E, Aypar U (2010). "Spinal 5-HT7 receptors play an important role in the antinociceptive and antihyperalgesic effects of tramadol and its metabolite, O-Desmethyltramadol, via activation of descending serotonergic pathways". Anesthesiology. 112 (3): 696–710. doi:10.1097/ALN.0b013e3181cd7920. PMID 20179508. 
  82. ^ Micó JA, Ardid D, Berrocoso E, Eschalier A (2006). "Antidepressants and pain". Trends in Pharmacological Sciences. 27 (7): 348–54. doi:10.1016/j.tips.2006.05.004. PMID 16762426. 
  83. ^ Leppert W (2011). "CYP2D6 in the metabolism of opioids for mild to moderate pain". Pharmacology. 87 (5–6): 274–85. doi:10.1159/000326085. PMID 21494059. 
  84. ^ Samer CF, Lorenzini KI, Rollason V, Daali Y, Desmeules JA (2013). "Applications of CYP450 testing in the clinical setting". Molecular Diagnosis & Therapy. 17 (3): 165–84. doi:10.1007/s40291-013-0028-5. PMC 3663206Freely accessible. PMID 23588782. 
  85. ^ "Tramadol Hydrochloride 50mg Capsules". UK Electronic Medicines Compendium. January 2016. Retrieved 16 March 2017. 
  86. ^ Pharmaceutical Substances, Axel Kleemann, Jürgen Engel, Bernd Kutscher and Dieter Reichert, 4. ed. (2000) 2 volumes, Thieme-Verlag Stuttgart (Germany), p. 2085 bis 2086, ISBN 978-1-58890-031-9; since 2003 online with biannual actualizations.
  87. ^ Zynovy Z, Meckler H (2000). "A Practical Procedure for the Resolution of (+)- and (−)-Tramadol". Organic Process Research & Development. 4 (4): 291–294. doi:10.1021/op000281v. 
  88. ^ Burke D, Henderson DJ (2002). "Chirality: a blueprint for the future". British Journal of Anaesthesia. 88 (4): 563–76. doi:10.1093/bja/88.4.563. PMID 12066734. 
  89. ^ Raffa RB, Friderichs E, Reimann W, Shank RP, Codd EE, Vaught JL, Jacoby HI, Selve N (1993). "Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol". J. Pharmacol. Exp. Ther. 267 (1): 331–40. PMID 8229760. 
  90. ^ Grond S, Meuser T, Zech D, Hennig U, Lehmann KA (1995). "Analgesic efficacy and safety of tramadol enantiomers in comparison with the racemate: a randomised, double-blind study with gynaecological patients using intravenous patient-controlled analgesia". Pain. 62 (3): 313–20. doi:10.1016/0304-3959(94)00274-I. PMID 8657431. 
  91. ^ Karhu D, El-Jammal A, Dupain T, Gaulin D, Bouchard S (2007). "Pharmacokinetics and dose proportionality of three Tramadol Contramid OAD tablet strengths". Biopharmaceutics & Drug Disposition. 28 (6): 323–30. doi:10.1002/bdd.561. PMID 17575561. 
  92. ^ Tjäderborn M, Jönsson AK, Hägg S, Ahlner J (2007). "Fatal unintentional intoxications with tramadol during 1995–2005". Forensic Sci. Int. 173 (2–3): 107–11. doi:10.1016/j.forsciint.2007.02.007. PMID 17350197. 
  93. ^ Baselt, R. (2011) Disposition of Toxic Drugs and Chemicals in Man, 9th edition, Biomedical Publications, Seal Beach, CA, pp. 1712–15, ISBN 978-0-9626523-8-7.
  94. ^ McCarberg B (2007). "Tramadol extended-release in the management of chronic pain". Therapeutics and clinical risk management. 3 (3): 401–10. PMC 2386353Freely accessible. PMID 18488071. 
  95. ^ US patent 6254887, Miller RB, Leslie ST, Malkowska ST, Smith KJ, Wimmer S, Winkler H, Hahn U, Prater DA, "Controlled Release Tramadol", issued 3 July 2001 
  96. ^ a b FDA AccessData entry for Tramadol Hydrochloride. Retrieved 17 August 2009.
  97. ^ US patent 7074430, Miller RB, Malkowska ST, Wimmer S, Hahn U, Leslie ST, Smith KJ, Winkler H, Prater DA, "Controlled Release Tramadol Tramadol Formulation", issued 11 July 2006 
  98. ^ "Par Pharmaceutical Wins on Invalidity in Ultram(R) ER Litigation" (Press release). Par Pharmaceutical. 17 August 2009. 
  99. ^ "DEA controls tramadol as a schedule IV controlled substance effective August 18, 2014". FDA Law Blog. 2 July 2014. 
  100. ^ "Federal Registrar" (PDF). gpo.gov. 
  101. ^ "TRAMADOL (Trade Names: Ultram®, Ultracet®)". Drug Enforcement Administration (February 2011)
  102. ^ "Tennessee News: Tramadol and Carisoprodol Now Classified Schedule IV". National Association of Boards of Pharmacy (8 June 2011). Retrieved on 2012-12-26.
  103. ^ "State of Ohio Board of Pharmacy" (PDF). Pharmacy.ohio.gov. 18 August 2014. Archived from the original (PDF) on 29 December 2016. Retrieved 8 November 2016. 
  104. ^ "Substansen tramadol nu narkotikaklassad på samma sätt som kodein och dextropropoxifen". Lakemedelsverket. 14 May 2008. Retrieved 18 April 2010. [permanent dead link]
  105. ^ "Tramadol to become a Controlled Drug in the UK". vetdispense.co.uk. 2 June 2014. Retrieved 3 June 2014. 
  106. ^ Harati Y, Gooch C, Swenson M, Edelman S, Greene D, Raskin P, Donofrio P, Cornblath D, Sachdeo R, Siu CO, Kamin M (1998). "Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy". Neurology. 50 (6): 1842–46. doi:10.1212/WNL.50.6.1842. PMID 9633738. 
  107. ^ Harati Y, Gooch C, Swenson M, Edelman SV, Greene D, Raskin P, Donofrio P, Cornblath D, Olson WH, Kamin M (2000). "Maintenance of the long-term effectiveness of tramadol in treatment of the pain of diabetic neuropathy". Journal of diabetes and its complications. 14 (2): 65–70. doi:10.1016/S1056-8727(00)00060-X. PMID 10959067. 
  108. ^ Barber J (2011). "Examining the use of tramadol hydrochloride as an antidepressant". Experimental and Clinical Psychopharmacology. 19 (2): 123–30. doi:10.1037/a0022721. PMID 21463069. 
  109. ^ Göbel H, Stadler T (1997). "[Treatment of post-herpes zoster pain with tramadol. Results of an open pilot study versus clomipramine with or without levomepromazine]". Drugs (in French). 53 Suppl 2: 34–39. doi:10.2165/00003495-199700532-00008. PMID 9190323. 
  110. ^ Boureau F, Legallicier P, Kabir-Ahmadi M (July 2003). "Tramadol in post-herpetic neuralgia: a randomized, double-blind, placebo-controlled trial". Pain. 104 (1–2): 323–31. doi:10.1016/S0304-3959(03)00020-4. PMID 12855342. 
  111. ^ Wu T, Yue X, Duan X, Luo D, Cheng Y, Tian Y, Wang K (2012). "Efficacy and safety of tramadol for premature ejaculation: a systematic review and meta-analysis". Urology. 80 (3): 618–24. doi:10.1016/j.urology.2012.05.035. PMID 22840860. 
  112. ^ Wong BL, Malde S (2013). "The use of tramadol "on-demand" for premature ejaculation: a systematic review". Urology. 81 (1): 98–103. doi:10.1016/j.urology.2012.08.037. PMID 23102445. 
  113. ^ Goldsmith TB, Shapira NA, Keck PE (1999). "Rapid remission of OCD with tramadol hydrochloride". American Journal of Psychiatry. 156 (4): 660–61. doi:10.1176/ajp.156.4.660a (inactive 2017-06-15). PMID 10200754. 
  114. ^ Boumendjel A, Sotoing Taïwe G, Ngo Bum E, Chabrol T, Beney C, Sinniger V, Haudecoeur R, Marcourt L, Challal S, Ferreira Queiroz E, Souard F, Le Borgne M, Lomberget T, Depaulis A, Lavaud C, Robins R, Wolfender JL, Bonaz B, De Waard M (November 2013). "Occurrence of the Synthetic Analgesic Tramadol in an African Medicinal Plant". Angewandte Chemie International Edition. 52 (45): 11780–84. doi:10.1002/anie.201305697. PMID 24014188. 
  115. ^ a b Kusari, S., Tatsimo, S. J. N., Zühlke, S., Talontsi, F. M., Kouam, S. F., Spiteller, M (2014). "Tramadol – A True Natural Product?". Angewandte Chemie International Edition. 53 (45): 12073. doi:10.1002/anie.201406639. PMID 25219922. 
  116. ^ Who Really did it First? Nature or a Pharmacist?, in Lab Times online; by Nicola Hunt; published September 22, 2014; retrieved November 21, 2015
  117. ^ Kusari, Souvik; Tatsimo, Simplice Joel N.; Zühlke, Sebastian; Spiteller, Michael (4 January 2016). "Synthetic Origin of Tramadol in the Environment". Angewandte Chemie International Edition. 55 (1): 240–43. doi:10.1002/anie.201508646. PMID 26473295. 
  118. ^ a b Souza MJ, Cox SK (2011). "Tramadol use in zoologic medicine". Vet Clin North Am Exot Anim Pract. 14 (1): 117–30. doi:10.1016/j.cvex.2010.09.005. PMID 21074707. 

External links

  • Medline Plus – Patient Information Medline Plus (A Service of the U.S. National Library of Medicine)
  • U.S. National Library of Medicine: Drug Information Portal – Tramadol
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