Tramadol (INN) (pronounced /ˈtræmədɒl/) is an atypical nonopioid which is a centrally acting analgesic, used for treating moderate to severe pain. It is a synthetic agent, as a 4-phenyl-piperidine analogue of codeine,^[1][2] and appears to have actions on the GABAergic, noradrenergic and serotonergic systems. Tramadol was developed by the German pharmaceutical company Grünenthal GmbH and marketed under the trade name Tramal. Grünenthal has also cross licensed the drug to many other pharmaceutical companies that market it under various names.

Tramadol is usually marketed as the hydrochloride salt (tramadol hydrochloride) and is available in both injectable (intravenous and/or intramuscular) and oral preparations. It is also available in conjunction with paracetamol (acetaminophen).

Tramadol is approximately 10% as potent as morphine, when given by the IV/IM route. Oral doses range from 50–400 mg daily, with up to 600 mg daily when given IV/IM. The formulation containing APAP contains 37.5 mg of tramadol and 325 mg of paracetamol, intended for oral administration with a common dosing recommendation of one or two tabs every four to six hours.

Tramadol is not considered a controlled substance in many countries (the U.S. and Australia, among others), and is available with a normal prescription. Tramadol is also available over-the-counter without prescription in a few countries.^[3]

Uses

Tramadol is used to treat moderate and severe pain.{Fact|date=February 2007}} It has been suggested that tramadol could be effective for alleviating symptoms of depression and anxiety because of its action on GABAergic, noradrenergic and specifically serotonergic systems. However, health professionals have not yet endorsed its use on a large scale for disorders such as this.^[4][5]

Off-label and investigational uses

• diabetic neuropathy^[6][7]
• postherpetic neuralgia^[8][9]
• fibromyalgia^[10]
• restless legs syndrome^[11]
• opiate withdrawal management^[12][13]
• migraine headache^[14]
• obsessive-compulsive disorder^[15]
• premature ejaculation^[16]

Veterinary

Tramadol is used to treat post-operative and/or chronic (e.g. cancer-related) pain in dogs and cats.[1]

Mechanism of action

The mode of action of tramadol has yet to be fully understood, but it is believed to work through modulation of the GABAergic, noradrenergic and serotonergic systems, in addition to its mild agonism of the μ-opioid receptor. The contribution of non-opioid activity is demonstrated by the analgesic effects of tramadol not being fully antagonised by the μ-opioid receptor antagonist naloxone.

Tramadol is marketed as a racemic mixture with a weak affinity for the μ-opioid receptor (approximately 1/6th that of morphine). The (+)-enantiomer is approximately four times more potent than the (-)-enantiomer in terms of μ-opioid receptor affinity and 5-HT reuptake, whereas the (-)-enantiomer is responsible for noradrenaline reuptake effects (Shipton, 2000). These actions appear to produce a synergistic analgesic effect, with (+)-tramadol exhibiting 10-fold higher analgesic activity than (-)-tramadol (Goeringer et al., 1997).

The serotonergic modulating properties of tramadol mean that it has the potential to interact with other serotonergic agents. There is an increased risk of serotonin syndrome 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. Tramadol is also thought to have some NMDA-type antagonist effects which has given it a potential application in neuropathic pain states.

Metabolism

Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2D6, being O- and N-demethylated to five different metabolites. Of these, M1 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. In the 6% of the population who have slow CYP2D6 activity, there is therefore a slightly reduced analgesic effect. Phase II hepatic metabolism renders the metabolites water-soluble and they are excreted by the kidneys. Thus reduced doses may be used in renal and hepatic impairment.

Adverse effects

The most commonly reported adverse drug reactions are dizziness, drowsiness, nausea, vomiting and sweating. Respiratory depression, a common side effect of most opioids, is not clinically significant in normal doses, because this medication is not considered an opiod. 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). 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" (Labate 2005). Dosages of coumadin/warfarin may need to be reduced for anticoagulated patients to avoid bleeding complications.

Dependence

Some controversy exists regarding the dependence liability of tramadol. Grünenthal has promoted it as a nonopioid with a lower risk of opioid dependence than that of traditional opioids, claiming little evidence of such dependence in clinical trials. They offer the theory that since the M1 metabolite is the principal agonist at μ-opioid receptors, the delayed agonist activity reduces dependence liability. The noradrenaline reuptake effects may also play a role in reducing dependence.

Despite these claims, it is apparent in community practice, that dependence to this agent does occur.^[17] However, this dependence liability is considered relatively low by health authorities, such that tramadol is classified as a Schedule 4 Prescription Only Medicine in Australia, rather than as a Schedule 8 Controlled Drug like other opioids (Rossi, 2004). Similarly, tramadol is not currently scheduled by the U.S. Nevertheless, the prescribing information for Ultram warns that tramadol "may induce psychological and physical dependence of the morphine-type". In addition, there are widespread reports by consumers of extremely difficult withdrawal experiences ^[18] including acute depression and suicidal urges. ^[19]

A controlled study that compared different medications found "the percent of subjects who scored positive for abuse at least once during the 12-month follow-up were 2.5% for NSAIDs, 2.7% for tramadol, and 4.9% for hydrocodone. When more than one hit on the dependency algorithm was used as a measure of persistence, abuse rates were 0.5% for NSAIDs, 0.7% for tramadol, and 1.2% for hydrocodone. Thus, the results of this study suggest that the prevalence of abuse/dependence over a 12-month period in a CNP population that was primarily female was equivalent for tramadol and NSAIDs, with both significantly less than the rate for hydrocodone".^[18]

Recreational use

As a nonopioid analgesic, tramadol can be used recreationally. It can, via agonism of μ opiate receptors, produce effects similar to those of opioids (e.g., morphine or hydrocodone), although not nearly as intense due to tramadol's much lower affinity for the receptor. However, the metabolite m1 is produced after demethylation of the drug in the liver. The m1 metabolite has an estimated 200x greater affinity for the mu1, and mu2 opioid receptors. In addition to acting as an opioid, tramadol is also a very weak but rapidly acting serotonin-norepinephrine reuptake inhibitor^[20]. When taken in amounts larger than normal therapeutic doses, tramadol can cause seizures (typically tonic-clonic) and severe nausea, which could deter abuse to some extent. Tramadol has been known to produce severe withdrawal symptoms with abrupt cessation after prolonged use. In addition, tramadol can help alleviate withdrawal symptoms from more addictive opiates, and is much easier to lower quantity of usage compared to opiates such as hydrocodone and oxycodone.^[18]

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:

• Adolan
• Adolonta
• Anadol
• Boldol (in Bosnia and Herzegovina)
• Calmador (in Argentina)
• Contramal
• Crispin
• Dolol (in Denmark)
• Ixprim (in France)
• Lumidol
• Mandolgin (in Denmark)
• Mandolgine
• Mosepan
• Nobligan
• Poltram
• Sintradon
• Siverol (in the Philippines)
• Tiparol
• Toplagic
• Tradol
• Tradolan
• Tradolan (in Sweden)
• Tradonal (in the Philippines)
• Tralgit
• Tralodie (in Italy)
• Tramacet
• Tramacip
• Tramadin
• Tramadolor
• Tramal (in the Netherlands,Slovenia and Romania)
• Tramalgic (in Hungary)
• Tramahexal
• Tramacet (combined with paracetamol)
• Tramazac (in India)
• Trama-Klosidol
• Tramedo
• Trodon (in Serbia)
• Ultracet (combined with paracetamol)
• Ultram and Ultram ER (in the US)
• Veldrol (in Mexico)
• Zaldiar (combined with paracetamol, in Russia)
• Zamudol
• Zydol (in the UK and Australia)
• Zytram
• Zytrim (in Spain)

Notable related deaths

• Rapper Russell Jones (a.k.a. Ol' Dirty Bastard) died from an overdose of a combination of cocaine and tramadol on November 13, 2004.^[21]

References