An overview on the dangers of tramadol abuse

[Paracelsus]

An overview on the dangers of tramadol abuse

0. Introduction

Tramadol is a synthetic opioid analgesic. It is commonly prescribed for moderate to severe pain, usual doses being up to 200 mg/day. The maximum allowed daily dose is 400 mg.

Tramadol provides analgesia through 3 mechanisms: mu-opioid binding (through its metabolite O-desmethyltramadol), serotonin reuptake inhibition (through (+)-tramadol) and norepinephrine reuptake inhibition (through (-)-tramadol). O-desmethyltramadol (which is formed from tramadol through O-demethylation catalyzed by CYP2D6) is responsible for the opiate-type effects of tramadol.

Tramadol abuse is becoming more and more popular, mainly because in most countries (including USA), tramadol is the only available non-scheduled opiate (with the exceptions of things like loperamide or some possible opiate research chemicals). If tramadol abuse will get public attention (through many hospitalizations and fatalities), this will change soon.

Being a seizure threshold-reducing drug, a serotonin reuptake inhibitor and an opioid, tramadol can be dangerous, especially when combined with the wrong substances. I will try to provide information about most known health risks of tramadol, without insisting on side effects such as dizziness, somnolence and constipation.

1. ‘Classic’ opiate health risks

Being an opioid, tramadol carries all possible risks known from other opiates. Tramadol causes respiratory depression, although usually weaker than that seen with other opiates and opioids. Tramadol can cause psychological and physical addiction similar to that of other opiates. Nausea, the possibility of choking on one’s own vomit, etc. Those experienced with opiates can probably are familiar with these and will usually be able to handle them.

2. Seizures

Seizures from tramadol occur at least once in about 0.87% of persons prescribed to tramadol. Risk factors included a history of drug abuse (which might involve high-dose use) and combining tramadol with other drugs.
Seizures are likely to be caused by tramadol itself. The risk of seizure increases with dosage (that is why the daily limit is 400 mg). Most reported seizures have been caused by exceeding this limit.
It can be concluded that seizures from tramadol are a real possibility, especially if it is used by the wrong persons, combined with wrong substances or used in high amounts.

3. Dangerous combinations with tramadol

3.1. ‘Classic’ opiate interactions

Being an opioid, tramadol shouldn’t be mixed with other depressants, because of increasing respiratory depression.

Also because it causes respiratory depression, tramadol should not be used recreationally by those suffering from asthma or other conditions which impair respiration.

3.2. Other serotoninergic drugs

Because it is a serotonin reuptake inhibitor, tramadol can cause serotonin syndrome when combined with other serotoninergics (drugs which raise serotonin levels). This has been reported with paroxetine, sertraline and dextromethorphan (all in therapeutic doses), and some others. Although serotonin syndrome is rarely fatal, some deaths have been attributed to combinations of tramadol and other serotoninergics (a handful, I didn’t count them – do a Pubmed search if you want more details).

Serotoninergic drugs include but are not limited to: most antidepressants (SSRIs, SNRIs, tricyclics, trazodone, nefazodone, etc.), MDMA and analogs (MDA, MDE, methylone, etc.), many phenethylamines and tryptamines (especially AMT, 5-MEO-AMT and AET), most amphetamines, cocaine, piperazines, DXM, some opioids (pethidine, fentanyl, propoxyphene, methadone), l-tryptophan and 5-HTP, lithium, 5HT agonists (triptans), etc. MAO inhibitors also keep serotonin levels raised, contributing to the possibility of serotonin syndrome.
Needless to say, if one has used one of these in the past two weeks, tramadol isn’t a good idea.

3.3. Other seizure threshold-reducing drugs (STRDs)

These can increase the chance of seizure if tramadol is used. Risk of seizure is dose-dependent.

STRDs include: anaesthetics (enflurane, isoflurane, propofol), antibiotics (penicillin, cephalosporins, amphotericins, imipenem), antidepressants (SSRIs, MAOIs, doxepin, nefazodone), antihistamines (azatadine, cyproheptadine, pheniramine, methdilazine, promethazine), triptans, antipsychotics, aminophylline and theophylline, DXM, bupropion, amphetamines, cocaine, all other stimulants (including caffeine), etc.

Other factors such as epilepsy, CRT monitors, withdrawal from sedatives (alcohol, barbiturates, benzodiazepines, GHB and analogs, etc.), use of brainwave generators, etc. also reduce the seizure threshold.

3.4. CYP2D6 inhibitors

Besides significantly weakening the opiate-like effects of tramadol, CYP2D6 inhibitors also increase the risk of serotonin syndrome and seizure, because these are caused by tramadol itself (and CYP2D6 inhibitors make the metabolization of tramadol slower).

CYP2D6 inhibitors include: fluoxetine, paroxetine, sertraline, chlorpheniramine, other first-generation antihistamines (in high doses), bupropion, amiodarone, haloperidol, ritonavir, indinavir, methadone, quinidine, celecoxib, cimetidine (Tagamet), DXM and codeine (the latter two are probably only relevant in recreational doses).

As a side note, codeine and tramadol has been reported to cause a seizure, while codeine after the tramadol peak (when levels of O-desmethyltramadol are highest) is reported to be quite enojyable (for both reports, search for "codeine tramadol synergy").

4. Who should not use tramadol

Epileptics should definitely stay away from tramadol because of very high risk of seizure. Because of this, physicians won’t prescribe it to epileptics anyway (otherwise go shoot your doc NOW). Persons with a history of seizures or a higher risk of seizures should also abstain from tramadol, even if they aren’t epileptics. This includes persons prescribed to any seizure threshold-reducing drugs (see 3.3.).

Persons who know to be CYP2D6 poor metabolizers shouldn’t even bother with tramadol – they won’t get any opiate-like effects from it, because much less O-desmethyltramadol is formed. If one doesn’t get any opiate-like effects from normally active doses of tramadol, that person COULD be CYP2D6 deficient.

Persons with a high tolerance to opiates should not use tramadol, because they won’t feel any opiate-like effects unless very high doses are consumed, which is dangerous because of the high risk of seizure. If one doesn’t get satisfactory effects from 300-400 mg, the dose should not be increased.

Persons who are physically addicted to any sedative (alcohol, barbiturates, benzodiazepines, GHB and analogs, etc.) should not use tramadol. If these are currently under the influence of the particular sedative, respiratory depression may become dangerous when tramadol is also consumed. If these are currently withdrawing from the particular sedative, the risk of seizures becomes extremely high.

Persons who have had an anaphylactoid reaction to any other opiate should be very cautious with tramadol.

Persons with severe renal or hepatic insufficiency should not use tramadol.

6. Tramadol deaths

25 deaths of adults involving tramadol have been reported. 20 of these are considered not to be caused by tramadol intoxication but by concomitant consumption of other drugs (mainly benzodiazepines and serotoninergics). 2 have been caused by tramadol alone, in concentrations 5- respectively 6-fold higher than the toxic level of tramadol (2 mg/L). So the main risk factor is combining tramadol with other substances, particularly sedatives and serotoninergics. Just say no.

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Reputation Comments on this post:

	Good!
	Great Post. We needed this.
	great info. solid post
	such informative posts!
	Sadly my doc didn't inform me on any of this, I could've certainly used the seizure and SSRI activity 2 years ago...