Tramadol

Systematic (IUPAC) name
(1R,2R)-rel-2-[(dimethylamino)methyl]- 1-(3-methoxyphenyl)cyclohexanol
Clinical data
Trade names	Ryzolt, Ultram
AHFS/Drugs.com	monograph
MedlinePlus	a695011
Pregnancy cat.	C (AU) C (US)
Legal status	Prescription Only (S4) (AU) POM (UK) ℞-only (US) ℞ Prescription only
Routes	Oral, IV, IM, rectal, sublingual, buccal, intranasal
Pharmacokinetic data
Bioavailability	68–72%(Increases with repeat dosing.)
Protein binding	20%
Metabolism	Hepatic demethylation and glucuronidation
Half-life	5.5–7 hours
Excretion	Renal
Identifiers
CAS number	27203-92-5 Y
ATC code	N02AX02
PubChem	CID 33741
DrugBank	DB00193
ChemSpider	31105 Y
UNII	39J1LGJ30J Y
KEGG	D08623 Y
ChEMBL	CHEMBL1066 Y
Chemical data
Formula	C16H25NO2
Mol. mass	263.4 g/mol
SMILES	eMolecules & PubChem
InChI InChI=1S/C16H25NO2/c1-17(2)12-14-7-4-5-10-16(14,18)13-8-6-9-15(11-13)19-3/h6,8-9,11,14,18H,4-5,7,10,12H2,1-3H3/t14-,16+/m1/s1 Y Key:TVYLLZQTGLZFBW-ZBFHGGJFSA-N Y
Y (what is this?)  (verify)

Tramadol hydrochloride (trademarked as Conzip, Ryzolt, Ultracet, Ultram in the USA,Ralivia and Zytram XL in Canada) is a centrally-acting synthetic analgesic used to treat moderate to moderately-severe pain. The drug has a wide range of applications, including treatment of rheumatoid arthritis, restless legs syndrome and fibromyalgia. It was launched and marketed as Tramal by the German pharmaceutical company Grünenthal GmbH in 1977.^[1][2]

Tramadol is a very weak μ-opioid receptor agonist, induces serotonin release, and inhibits the reuptake of norepinephrine.^[3][4] Tramadol is converted to O-desmethyltramadol, a significantly more potent μ-opioid agonist. The opioid agonistic effect of tramadol and its major metabolite(s) is almost exclusively mediated by such μ-opioid receptors. This further distinguishes tramadol from opioids in general (including morphine), which do not possess tramadol's degree of receptor subtype selectivity and which are much stronger opiate-receptor agonists. Similarly, the habituating properties of tramadol (such as they are) are arguably mainly due to μ-opioid agonism with contributions from serotonergic and noradrenergic effects.

Medical uses[link]

Tramadol is used similarly to codeine, to treat moderate to moderately severe pain.^[5] Pharmacologically, Tramadol is similar to levorphanol (albeit with much lower μ-agonism), as both agents are also NMDA-antagonists with SNRI activity. Dextropropoxyphene (Darvon) & M1-like molecule tapentadol (Nucynta, a new synthetic atypical opioid made to mimic the agonistic properties of tramadol's metabolite, M1(O-Desmethyltramadol)) also have similar activities. Tramadol is also molecularly similar to venlafaxine (Effexor) and has similar SNRI effects, with antinociceptive effects. It has been suggested that tramadol could be effective for alleviating symptoms of depression, anxiety, and phobias^[6] because of its action on the noradrenergic and serotonergic systems, such as its "atypical" opioid activity.^[7] However, health professionals have not endorsed its use for these disorders,^[8][9] claiming it may be used as a unique treatment (only when other treatments failed), and must be used under the control of a psychiatrist.^[10][11]

In May 2009, the United States Food and Drug Administration issued a Warning Letter to Johnson & Johnson, alleging that a promotional website commissioned by the manufacturer had "overstated the efficacy" of the drug, and "minimized the serious risks".^[12] The company which produced it, the German pharmaceutical company Grünenthal GmbH, were alleged to be guilty of "minimizing" the habituating nature of the drug, although it showed little abuse liability in preliminary tests.^{[citation needed]} The 2010 Physicians Desk Reference contains several warnings from the manufacturer, which were not present in prior years. The warnings include stronger language regarding the habituating potential of tramadol, the possibility of difficulty breathing while on the medication, a new list of more serious side effects, and a notice that tramadol is not to be used in place of opiate medications for addicts. Tramadol is also not to be used in efforts to wean addict patients from opiate drugs, nor to be used to manage long-term opiate addiction.

Availability and usage[link]

100mg tramadol injection, marketed by the original 'Contramal' trade-mark owner, Grünenthal GmbH.(Hungarian release)

50 mg Tramadol HCl tablets (generic Ultram) marketed by Akyma Pharmaceuticals. Immediate release tramadol HCl is available in many generic preparations.

Bottle of 30 tablets of 200 mg extended-release tramadol HCl (generic Ultram ER) marketed by Patriot. Extended-release tramadol is commonly available in 100, 200, and 300 mg strengths to be taken once daily. It is often prescribed with tramadol-APAP (Ultracet) or regular immediate-release tramadol HCl (Ultram/Tramal/Rybix) for breakthrough pain.^[13]

Tramadol HCl for injection

Tramadol is classified as a central nervous system drug usually marketed as the hydrochloride salt (tramadol hydrochloride); the tartrate is seen on rare occasions, and rarely (in the US at least) tramadol is available for both injection (intravenous and/or intramuscular) and oral administration. The most well known dosing unit is the 50 mg generic tablet made by several manufacturers. It is also commonly available in conjunction with APAP (paracetamol, acetaminophen) as Ultracet, in the form of a smaller dose of 37.5 mg tramadol and 325 mg of APAP. The solutions suitable for injection are used in patient-controlled analgesia pumps under some circumstances, either as the sole agent or along with another agent such as morphine.

Tramadol comes in many forms, including:

• capsules (regular and extended release)
• tablets (regular, extended release, chewable, low-residue and/or uncoated tablets that can be taken by the sublingual and buccal routes)
• suppositories
• effervescent tablets and powders
• ampules of sterile solution for SC, IM, and IV injection
• preservative-free solutions for injection by the various spinal routes (epidural, intrathecal, caudal, and others)
• powders for compounding
• liquids both with and without alcohol for oral and sub-lingual administration, available in regular phials and bottles, dropper bottles, bottles with a pump similar to those used with liquid soap and phials with droppers built into the cap
• tablets and capsules containing (acetaminophen/APAP), aspirin and other agents.

Tramadol is regularly used in the form of an ingredient in multi-agent topical gels, creams, and solutions for nerve pain, rectal foam, concentrated retention enema, and a skin plaster (transdermal patch) quite similar to those used with lidocaine.

Tramadol has a characteristic and unpleasant taste which is mildly bitter but much less so than morphine and codeine. Oral and sublingual drops and liquid preparations come with and without added flavoring. Also, 50 mg water-soluble tramadol tablets has strawberry-flavouring, no matter which company manufactured it, to distinguish every, same-looking and same sized Mirtazapine sublingual tablets, which has orange flavouring irrespective of the manufacturer. This different flavouring is considered to be a standard. Its relative effectiveness via transmucosal routes (i.e. sublingual, buccal, rectal) is similar to that of codeine, and, like codeine, it is also metabolized in the liver to stronger metabolites (see below).

The maximum dosage per day is 400 mg for oral use and 600 mg for parenteral use. Certain manufacturers or formulations have lower maximum doses. For example, Ultracet (37.5 mg/325 mg tramadol/APAP tablets) is capped at 8 tablets per day (300 mg/day) due to its acetaminophen content. Ultram ER is available in 100, 200, and 300 mg/day doses and is explicitly capped at 300 mg/day as well.

Patients taking SSRIs (Prozac, Zoloft, etc.), SNRIs (Effexor, etc.), TCAs, MAOIs, or other strong opioids (oxycodone, methadone, fentanyl, morphine), as well as the elderly (> 75 years old), pediatric (< 18 years old), and those with severely reduced renal (kidney) or hepatic (liver) function should consult their doctor regarding adjusted dosing or whether to use tramadol at all.

Investigational uses[link]

• diabetic neuropathy ^[14][15]
• antidepressant ^[16]
• postherpetic neuralgia ^[17][18]
• acute opioid withdrawal management^[19][20]
• antidepressant withdrawal aid (proven to be effective, especially with withdrawal from its distant relative venlafaxine (Effexor)).^{[citation needed]}
• obsessive-compulsive disorder ^[21]
• premature ejaculation^[22]

Adverse effects[link]

Main side effects of tramadol. Red color denotes more serious effects, requiring immediate contact with health provider.^[25]

The most commonly reported adverse drug reactions are nausea, vomiting, sweating, itching and constipation. Drowsiness is reported, although it is less of an issue than for opioids per se. Patients prescribed tramadol for general pain relief with or without other agents have reported withdrawal symptoms including uncontrollable nervous tremors, muscle contracture, and 'thrashing' in bed (similar to restless leg syndrome) if weaned off the medication too quickly. Anxiety, 'buzzing', 'electrical shock' and other sensations may also be present, similar to those noted in Effexor withdrawal. Respiratory depression, a common side-effect of most opioids, is not clinically significant in normal doses. By itself, it can decrease the seizure threshold. When combined with SSRIs, tricyclic antidepressants, or in patients with epilepsy, the seizure threshold is further decreased. Seizures have been reported in humans receiving excessive single oral doses (700 mg) or large intravenous doses (300 mg). However, there have been several rare cases of people having grand-mal seizures at doses as low as 100–400 mg orally.^[26][27][28] An Australian study found that of 97 confirmed new-onset seizures, eight were associated with tramadol, and that in the authors' First Seizure Clinic, "tramadol is the most frequently suspected cause of provoked seizures".^[29] There appears to be growing evidence that tramadol use may have serious risks in some individuals and it is contra-indicated in patients with uncontrolled epilepsy (BNF 59). Seizures caused by tramadol are most often tonic-clonic seizures, more commonly known in the past as grand mal seizures. Also when taken with SSRIs, there is an increased risk of serotonin toxicity, which can be fatal.

Fewer than 1% of users have a presumed incident seizure claim after their first tramadol prescription. Risk of seizure claim increases two- to six-fold among users adjusted for selected comorbidities and concomitant drugs. Risk of seizure is highest among those aged 25–54 years, those with more than four tramadol prescriptions, and those with a history of alcohol abuse, stroke, or head injury.^[24] Dosages of warfarin may need to be reduced for anticoagulated patients to avoid bleeding complications. Constipation can be severe especially in the elderly requiring manual evacuation of the bowel.^{[citation needed]} Furthermore, there are suggestions that chronic opioid administration may induce a state of immune tolerance,^[30] although tramadol, in contrast to typical opioids may enhance immune function.^[31][32][33] Some have also stressed the negative effects of opioids on cognitive functioning and personality.^[34]

Physical dependence and withdrawal[link]

Long-term use of high doses of Tramadol may be associated with physical dependence and a withdrawal syndrome.^[35] Tramadol causes typical opiate-like withdrawal symptoms as well as atypical withdrawal symptoms including seizures. The atypical withdrawal symptoms are probably related to tramadol's effect on serotonin and norepinephrine re-uptake. Symptoms may include those of SSRI discontinuation syndrome, such as anxiety, depression, anguish, severe mood swings, aggressiveness, brain "zaps", electric-shock-like sensations throughout the body, paresthesias, sweating, palpitations, restless legs syndrome, sneezing, insomnia, vivid dreams or nightmares, micropsia and/or macropsia, tremors, and headache among others. In most cases, tramadol withdrawal will set in 12–20 hours after the last dose, but this can vary. Tramadol withdrawal 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. It is recommended that patients physically dependent on pain killers take their medication regularly to prevent onset of withdrawal symptoms and this is particularly relevant to tramadol because of its SSRI and SNRI properties, and, when the time comes to discontinue their tramadol, to do so gradually over a period of time that will vary according to the individual patient and dose and length of time on the drug.^{[36][37][38][39]}

Psychological dependence and recreational use[link]

Some controversy regarding the abuse potential of tramadol exists. Grünenthal has promoted it as having a lower risk of opioid dependence than traditional opioids, claiming little evidence of such dependence in clinical trials (which is true; Grünenthal never claimed it to be non-addictive). They offer the theory that, since the M1 metabolite is the principal agonist at μ-opioid receptors, the delayed agonist activity reduces abuse liability. The norepinephrine reuptake inhibitor effects may also play a role in reducing dependence.

Rarely, dependence may occur after as little as three months of use at the maximum dose—generally depicted at 400 mg per day. However, both physicians and health authorities generally consider dependence liability relatively low. Thus, tramadol is classified as a Schedule 4 Prescription Only Medicine in Australia, and been rescheduled in Sweden rather than as a Schedule 8 Controlled Drug like opioids.^[40] Similarly, unlike opioid analgesics, tramadol is not currently scheduled as a controlled substance by the U.S. DEA. However, it is scheduled in certain states.^[41] Nevertheless, the prescribing information for Ultram warns that tramadol "may induce psychological and physical dependence of the morphine-type". Using tramadol as recreational drug may also be preferred because it is one of the only opioids that is often not screened for by standard urine drug-tests.

Dependence on tramadol has been reported to be a major social problem in the Gaza Strip. The Hamas government has attempted to cut off supplies of the drug, and in April 2010 burnt 2 million tablets which had been intercepted while being smuggled into the territory.^[42]

Because of the possibility of convulsions at high doses for some users, recreational use can be very dangerous.^[43] However, via agonism of μ opioid receptors, Tramadol can produce effects similar to those of other opioids (codeine and other weak opioids). Due to tramadol's much lower affinity for this receptor, these are not nearly as intense as with the opiates per se. Tramadol can cause a higher incidence of nausea, dizziness, loss of appetite compared with opiates, which could deter abuse.^[44] Tramadol can alleviate withdrawal symptoms from opiates, and it is much easier to control its usage than for street drugs.^[45] It may also have large effect on sleeping patterns and high doses may cause insomnia. (Especially for those on methadone, both for maintenance and recreation. Though there is no scientific proof tramadol lessens effects of opiates or is a mixed agonist-antagonist, some people get the impression it is, while someone else might benefit being prescribed both for pain and breakthrough pain.)^[46]

Detection in biological fluids[link]

Tramadol and O-desmethyltramadol may be quantitated in blood, plasma or serum to monitor for abuse, confirm a diagnosis of poisoning or assist in the forensic investigation of a traffic or other criminal violation or 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 concentrations of O-desmethyltramadol in the blood or plasma of a person who has taken tramadol are generally 10–20% those of the parent drug.^[47][48][49]

Mechanism of action[link]

Tramadol acts as a μ-opioid receptor agonist,^[50][51] serotonin releasing agent,^{[3][4][52][53]} norepinephrine reuptake inhibitor,^[51] NMDA receptor antagonist,^[54] 5-HT_2C receptor antagonist,^[55] (α7)₅ nicotinic acetylcholine receptor antagonist,^[56] TRPV1 receptor agonist,^[57] and M₁ and M₃ muscarinic acetylcholine receptor antagonist.^[58][59]

The analgesic action of tramadol is not fully understood, but it is believed to work through modulation of serotonin and norepinephrine in addition to its relatively-weak μ-opioid receptor agonism. The contribution of non-opioid activity is demonstrated by the fact that the analgesic effect of tramadol is not fully antagonised by the μ-opioid receptor antagonist naloxone.

Tramadol is marketed as a racemic mixture of the (1R,2R)- and (1S,2S)-enantiomers with a weak affinity for the μ-opioid receptor (approximately 1/6000th that of morphine; Gutstein & Akil, 2006). The (1R,2R)-(+)-enantiomer is approximately four times more potent than the (1S,2S)-(–)-enantiomer in terms of μ-opioid receptor affinity and 5-HT reuptake, whereas the (1S,2S)-(–)-enantiomer is responsible for noradrenaline reuptake effects (Shipton, 2000). These actions appear to produce a synergistic analgesic effect, with (1R,2R)-(+)-tramadol exhibiting 10-fold higher analgesic activity than (1S,2S)-(–)-tramadol (Goeringer et al., 1997).

The serotonergic-modulating properties of tramadol give it the potential to interact with other serotonergic agents. There is an increased risk of serotonin toxicity when tramadol is taken in combination with serotonin reuptake inhibitors (e.g., SSRIs), since these agents not only potentiate the effect of 5-HT but also inhibit tramadol metabolism.^{[citation needed]} Tramadol is also thought to have some NMDA antagonistic effects, which has given it a potential application in neuropathic pain states.

Tramadol has inhibitory actions on the 5-HT_2C receptor. Antagonism of 5-HT_2C could be partially responsible for tramadol's reducing effect on depressive and obsessive-compulsive symptoms in patients with pain and co-morbid neurological illnesses.^[60] 5-HT_2C blockade may also account for its lowering of the seizure threshold, as 5-HT_2C 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 GABA-A receptors at high doses.^[54]

The overall analgesic profile of tramadol supports use in the treatment of intermediate pain, especially chronic pain. It is slightly less effective for acute pain than hydrocodone, but more effective than codeine. It has a dosage ceiling similar to codeine, a risk of seizures when overdosed, and a relatively long half-life making its potential for misuse relatively low amongst intermediate strength analgesics.

Tramadol's primary active metabolite, O-desmethyltramadol, is a considerably more potent μ-opioid receptor agonist than tramadol itself. Thus, tramadol is in part a prodrug to O-desmethyltramadol. Similarly to tramadol, O-desmethyltramadol has also been shown to be a norepinephrine reuptake inhibitor, 5-HT_2C receptor antagonist, and M₁ and M₃ muscarinic acetylcholine receptor antagonist.^{[citation needed]}

Chemistry[link]

Characteristics[link]

Structurally, tramadol closely resembles a stripped down version of codeine. Both codeine and tramadol share the 3-methyl ether group, and both compounds are metabolized along the same hepatic pathway and mechanism to the stronger opioid, phenol agonist analogs. For codeine, this is morphine, and for tramadol, it is the O-desmethyltramadol.

Comparison with related substances[link]

Structurally, tapentadol is the closest chemical relative of tramadol in clinical use. Tapentadol is also an opioid, but unlike both tramadol and venlafaxine, tapentadol represents only one stereoisomer and is the weaker of the two, in terms of opioid effect. Both tramadol and venlafaxine are racemic mixtures. Structurally, tapentadol also differs from tramadol in being a phenol, and not an ether. Also, both tramadol and venlafaxine incorporate a cyclohexyl moiety, attached directly to the aromatic, while tapentadol lacks this feature. In reality, the closest structural chemical entity to tapentadol in clinical use is the over-the-counter drug phenylephrine. Both share a meta phenol, attached to a straight chain hydrocarbon. In both cases, the hydrocarbon terminates in an amine.

Synthesis and stereoisomerism[link]

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

The chemical synthesis of tramadol is described in the literature.^[61] 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^[62] 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 ^[63] of the (1R,2R)- and (1S,2S)-isomers, because the racemate showed higher analgesic activity than either enantiomer in animals^[64] and in humans.^[65]

Metabolism[link]

Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2B6, CYP2D6 and CYP3A4, being O- and N-demethylated to five different metabolites. Of these, 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 increased CYP2D6 activity (increased metabolism), there is therefore an increased analgesic effect. Those with decreased CYP2D6 activity will experience less analgesia. 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.^[66]

Legal status[link]

Tramadol (as the racemic, cis-hydrochloride salt), is available as a generic in the U.S. from any number of different manufacturers, including Amneal, Caraco, Mylan, Cor Pharma, Mallinckrodt, Pur-Pak, APO, Teva, and many more. Typically, the generic tablets are sold in 50 mg tablets. Brand name formulations include Ultram ER, and the original Ultram from Ortho-McNeil (cross-licensed from Grünenthal GmbH). The extended-release formulation of tramadol—which, amongst other factors—was intended to be more abuse-deterrent than the instant release) allegedly possesses more abuse liability than the instant release formulation.^{[citation needed]} The U.S. Food and Drug Administration (FDA) approved tramadol in March 1995 and an extended-release (ER) formulation in September 2005.^[67] It is covered by U.S. patents nos. 6,254,887^[68] and 7,074,430.^[69][70] The FDA lists the patents as scheduled for expiration on May 10, 2014.^[69] However, in August 2009, U.S. 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.^[71]

Although Tramadol is not a federally controlled substance in the United States, Kentucky and Arkansas have classified Tramadol as a schedule 4 controlled substance under state law. ^[72] Sweden, as of May 2008, has chosen to classify tramadol as a controlled substance in the same way as codeine and dextropropoxyphene. This means that the substance is a scheduled drug. But unlike codeine and dextropropoxyphene, a normal prescription can be used at this time.^[73] In Mexico, combined with paracetamol and sold under the brand name Tramacet, it is widely available without a prescription. In most Asian countries such as the Philippines, it is sold as a capsule under the brand name Tramal, where it is mostly used to treat labor pains.

Proprietary preparations[link]

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

Veterinary medicine[link]

Tramadol may be used to treat post-operative, injury-related, and chronic (e.g., cancer-related) pain in dogs and cats^[74] as well as rabbits, coatis, many small mammals including rats and flying squirrels, guinea pigs, ferrets, and raccoons. Tramadol comes in ampules in addition to the tablets, capsules, powder for reconstitution, and oral syrups and liquids; the fact that its characteristic taste is distasteful to dogs, but can be masked in food, makes for a means of administration. No data that would lead to a definitive determination of the efficacy and safety of tramadol in reptiles or amphibians are available, and, following the pattern of all other drugs, it appears that tramadol can be used to relieve pain in marsupials, such as North American opossums, Short-Tailed Opossums, sugar gliders, wallabies, and kangaroos among others.

Tramadol for animals is one of the most reliable and useful active principles available to veterinarians for treating animals in pain. It has a dual mode of action: mu agonism and mono-amine reuptake inhibition, which produces mild anti-anxiety results. Tramadol may be used for relieving pain in cats and dogs. This is an advantage because the use of some non-steroidal anti-inflammatory substances in these animals may be dangerous.

When animals are administered tramadol, adverse reactions can occur. The most common are constipation, upset stomach, decreased heart rate. In case of overdose, mental alteration, pinpoint pupils and seizures may appear. In such cases, veterinarians should evaluate the correct treatment for these events. Some contraindications have been noted in treated animals taking certain other drugs. Tramadol should not be co-administered with selegiline or any other psychoactive class of medication such as selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, or monoamine oxidase inhibitors. In animals, tramadol is removed from the body via liver and kidney excretion. Animals suffering from diseases in these systems should be monitored by a veterinarian, as it may be necessary to adjust the dose.

References[link]

External links[link]

• 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

Francis Martin Patrick "Frankie" Boyle^[1] (born 16 August 1972) is a Scottish^[2] comedian and writer, well known for his pessimistic, often controversial sense of humour. He was a permanent panellist on Mock the Week for seven series and has made guest appearances on several popular panel shows including Have I Got News for You, 8 Out of 10 Cats, Would I Lie to You?, You Have Been Watching, Never Mind the Buzzcocks (as guest host and team captain when Phill Jupitus was unavailable for recording) and Argumental, as well as writing for Jimmy Carr's show Distraction and Sean Lock's TV Heaven, Telly Hell.

Early life[link]

Boyle was born and brought up in Glasgow. After leaving school he attended Aston University for a year before leaving and starting a BA in English at the University of Sussex. Whilst doing a teacher-training course in Edinburgh at the age of 23, he began doing stand-up routines.^[3] He got his big break after performing at The Stand Comedy Club in Edinburgh, a venue that has also helped launch the careers of Stewart Lee, Johnny Vegas, Dara Ó Briain and Michael McIntyre.^[4]

Career[link]

Television[link]

Boyle was a regular on the BBC panel show Mock The Week until October 2009, a show in which the panel comment humorously on various news stories from the British media. He has been referred to as the 'dark heart of Mock the Week' by host Dara Ó Briain.^[5] He is known for his morbid sense of humour, which plays on negative images of society (particularly his country of birth, Scotland), celebrities and politicians.

On 2 October 2009 he announced he was leaving the show to concentrate on other projects. It was announced to the public via Facebook on the Mock the Week fan page.^[6][7][8] Boyle has since criticised both the show's production team and the BBC Trust. He claims that the show did not cover enough major news stories and was too restrictive on his risqué comedy act, as the producers and the BBC Trust were afraid of "frightening the horses".^[9]

He returned to Mock The Week for his final appearance on the 2009 Christmas Special which aired on 22 December 2009 as a series of best bits and festive clips. On 9 December 2009 he appeared as the guest host of Never Mind The Buzzcocks.^[10]

[edit] Frankie Boyle's Tramadol Nights

In October 2009 Boyle piloted a sketch and stand-up show for Channel 4, entitled Deal With This, Retards to be produced by RDF Scotland subsidiary the Comedy Unit.^[11] Boyle mentioned on Friday Night With Jonathan Ross that the original title of the show had been dropped, due to its potentially offensive nature. The programme was renamed Tramadol Nights and aired from the end of November 2010.^[12] An official page launched via Channel 4's official website, which confirmed that the show's full name is Frankie Boyle's Tramadol Nights and the series was made up of six episodes.^[13] Boyle has caused controversy with his on-air comments about Katie Price and her disabled son, Harvey.

Books[link]

On October 1, 2009, Boyle's first autobiographical book, titled My Shit Life So Far, was released,^[14] published by HarperCollins.^[15]

His second book, Work! Consume! Die!, was released in October 2011.

Journalism[link]

It was reported on 24 October 2008 that Boyle was to begin a weekly column in the Daily Record, a Scottish tabloid newspaper.^[16] On 26 June 2009, he reported via his MySpace profile that he had quit his newspaper column as "they refused to print any Michael Jackson jokes." This message was followed by the article he wanted to be printed, which contained dozens of Michael Jackson-based jokes referring to the singer's health, childhood and paedophilia charges.^[17] Frankie Boyle now writes articles in The Sun, satirising the weekly news as he did previously on Mock The Week.

Live shows[link]

In October 2007 Boyle embarked on a long stand-up tour of Britain, playing over 100 dates and enjoying a sold-out run that was extended through until December 2008. Boyle plans to quit stand-up before he turns 40, and has stated that he has written his final tour and plans to do more TV work after this.^[18] Boyle performed the tour, entitled I Would Happily Punch Every One Of You In The Face between March and December 2010.^[19]

On 21 November 2011, at a Meet the Comedians session in the Apple Store, Regent Street with Jimmy Carr,^[20] Boyle announced he was doing another tour entitled The Last Days of Sodom despite intending I Will Happily Punch Every One Of You In The Face to be his final one. He mentioned the tour will not be as long as its predecessor. His website has stated it will run from July to December 2012 with more dates to be added.^[21] Tickets went on sale in December 2011.^[22]

DVD releases[link]

On 10 November 2008 Boyle's first DVD was released,^[5] featuring a sell-out stand-up performance given at London's Hackney Empire and some additional material, including a documentary about the tour, entitled Fuck You Scotland, and some sketches from the BBC3 comedy Rush hour.^[23] The DVD was described by WhatDVD.net as "certainly not one to watch with your grandparents – not unless they are pretty open-minded!"^[24]