Tramadol

There is a high incidence of death due to respiratory depression when opiates are combined with depressants such as benzodiazepines, alcohol or other GABAergic substances.

Tramadol
The skeletal formula of tramadol
Chemical Nomenclature
Common names	Tramadol
Systematic name	2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
Class Membership
Psychoactive class	Depressant
Chemical class	Opioid
Routes of Administration
Oral Dosage WARNING: Always start with lower doses due to differences between individual body weight, tolerance, metabolism, and personal sensitivity. Threshold 50 mg Light 50 - 100 mg Common 75 - 200 mg Strong 200 - 300 mg Heavy 300 mg+ Duration Total 6 - 14 hours Onset 15 - 60 minutes Peak 2 - 8 hours Offset 4 - 6 hours Afterglow 1 - 5 hours

Summary sheet: Tramadol

Tramadol (Ultram, Ralivia) is a centrally acting opioid analgesic used to treat moderate to moderately severe pain. It was launched and marketed as Tramal by the German pharmaceutical company Grünenthal GmbH in 1977 in West Germany, even though it would take another 20 years for it to be launched in English-speaking countries such as the UK, US and Australia.

Tramadol is marketed as a racemic mixture of both R and S stereoisomers. This is because the two isomers compliment each other's analgesic activity. It is often combined with paracetamol as this is known to improve the efficacy of tramadol in relieving pain. Tramadol is a reuptake inhibitor of norepinephrine and serotonin and a weak μ-opioid receptor agonist. Tramadol is metabolised to O-Desmethyltramadol, a significantly more potent opioid.

For a period of time it was believed tramadol was not a purely synthetic drug after its apparent discovery in the roots of the pin cushion tree. These reports later proved to be erroneous; the tramadol had been excreted by cows treated with the drug, resulting in the tramadol having seeped into the roots through their urine.

Chemistry

(+/-)Tramadol, or 2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol, is an atypical synthetic opioid. Tramadol is loosely analogous to codeine, but is not a morphinan opiate. Instead, tramadol contains two rings that include a cyclohexane ring bonded to a phenyl ring at R₁. This phenyl ring is substituted at R₃ with a methoxy group (CH₃O-). At the same location (R₁) the cyclohexane ring is bonded to the phenyl ring, an additional hydroxy group is found. Tramadol features a second substitution on its cyclohexane ring at R₂. Here, the ring is bonded to a dimethylamine group connected through a methyl bridge.

Tramadol is unique as it is found in a racemate (combination) of its stereoisomers. These are two molecules that share the same chemical structure, but are three-dimensional mirror images of each other. Tramadol is produced as a racemate of its two isomers because the combination is proven to be more effective. The picture seen above is the R- enantiomer of tramadol, switching the dashed and solid wedges seen on the molecule skeleton results in the S- enantiomer. It is produced as a hydrochloride salt.

Pharmacology

The R- and S- enantiomers of tramadol act on different receptors in a complimentary manner. The R- enantiomer is a selective agonist of the mu receptors and inhibits serotonin reuptake while the S- enantiomer inhibits noradrenaline release. Tramadol acts as an opioid receptor agonist, serotonin releasing agent, norepinephrine reuptake inhibitor, NMDA receptor antagonist, 5-HT2C receptor antagonist, (α7)5 nicotinic acetylcholine receptor antagonist, TRPV1 receptor agonist, and M1 and M3 muscarinic acetylcholine receptor antagonist.

The euphoric effects of this compound appear to stem from the way in which opioids mimic endogenous endorphins. Endorphins are responsible for analgesia (reducing pain), causing sleepiness, and feelings of pleasure. They can be released in response to pain, strenuous exercise, orgasm, or excitement. This mimicking of natural endorphins results in the drug's euphoric, analgesic (pain relief), and anxiolytic (anti-anxiety) effects.

Subjective effects

The effects listed below are based upon the subjective effects index and personal experiences of PsychonautWiki contributors. The listed effects will rarely (if ever) occur all at once, but heavier dosages will increase the chances and are more likely to induce a full range of effects.

Physical effects

The cognitive effects of tramadol can be broken down into several components which progressively intensify proportional to dosage. The general head space of codeine is described by many as one of intense euphoria, relaxation, anxiety suppression and pain relief.

The most prominent of these cognitive effects generally include:

• Pain relief - This component is subjectively different from other anaesthetics as it does not necessarily remove the pain entirely whilst still remaining equal in terms of its effectiveness. Instead of directly suppressing pain these substances simply dull the perceived sensation and cover it up with feelings of physical and emotional pleasure.
• Physical euphoria - This particular substance can be considered as less intense in its physical euphoria when compared with that of morphine or diacetylmorphine (heroin). The sensation itself can be described as extreme feelings of hyper intense physical comfort, snugglyness, warmth, love and blissful euphoria.
• Itchiness - It presents greater amounts of itchiness due to higher amounts of histamine release.
• Stimulation - This compound is considerably more stimulating than that of codiene and diacetylmorphine due to its effects as a serotonin reuptake inhibitor.
• Constipation
• Cough suppression
• Difficulty urinating
• Nausea
• Sedation
• Pupil constriction

Cognitive effects

The physical effects of tramadol can be broken down into three components which progressively intensify proportional to dosage.

These are described below and generally include:

• Cognitive euphoria - This particular substance can be considered as less intense in its cognitive euphoria when compared with that of morphine or diacetylmorphine (heroin). The sensation itself can be described as powerful and overwhelming feeling of emotional bliss, contentment, and happiness.
• Anxiety suppression
• Compulsive redosing

Toxicity and harm potential

Tramadol has not been shown to be toxic and is physically benign at reasonable dosages. As with all opiates, long-term effects can vary but can include diminished libido, apathy and memory loss.

Tolerance and addiction potential

Tolerance to many of the effects of tramdol develops with prolonged use, including therapeutic effects. The rate at which this occurs develops at different rates for different effects, with tolerance to the constipation-inducing effects developing particularly slowly for instance.

As with other opiate-based painkillers, chronic use of tramadol can be considered as highly addictive and is capable of causing both physical and psychological dependence. When physical dependence has developed, withdrawal symptoms may occur if a person suddenly stops their usage.

Interactions

Tramadol's serotonergic effects enable it to interact, potentially fatally, with other serotonergics such as antidepressants (such as monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, noradrenergic and specific serotonergic antidepressants, serotonin antagonist and reuptake inhibitors, etc.), certain analgesics (such as pethidine (meperidine), tapentadol, oxycodone, dextromethorphan and fentanyl), certain anxiolytics (such as the SSRIs and buspirone), certain antibiotics (namely, linezolid and isoniazid), certain herbs (e.g., St. John's wort, syrian rue, passiflora, etc.), certain recreational drugs (e.g., MDMA), phentermine, lithium, methylene blue and numerous other therapeutic agents. 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.

Legal issues

• USA: In November 2013, the United States Drug Enforcement Administration initiated classification of Tramadol as a Schedule IV controlled substance, pending a review process. Several states, including Arkansas, Kentucky, Illinois, Mississippi, New York, North Dakota, Oklahoma, Tennessee, West Virginia, Wyoming and the U.S. military have classified Tramadol as a Schedule IV controlled substance under state law.
• Sweden: As of May 2008, Sweden 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.
• U.K.: On June 10th, 2014, tramadol was made a Class C drug under The Misuse of Drugs Act.

See also

• Responsible use
• Opioids
• Codeine
• Tramadol (Wikipedia)
• Tramadol (Erowid)