(2003; 31 pages) [French] [Spanish]
3.6 Tramadol (INN)
Tramadol, chemically (+/-)trans-2-dimethylaminomethyl-1-(3-methoxyphenyl) cyclohexanol), is available as either the free base (CAS 27203-92-5) or as the hydrochloride salt (CAS 36282-47-0). It is marketed under over 100 trade names.
Tramadol was pre-reviewed at the twenty-eighth meeting of the Committee at which time critical review was not recommended (9); however following pre-review at the thirty-second meeting, critical review was recommended (4).
Similarity to known substances and effects on the central nervous system
Tramadol has been found to be an opioid agonist with selectivity for the μ-opioid receptor but with some weak affinity for the k- and δ-opioid receptors. The affinity for the μ-opioid receptor is approximately 10-fold less than that of codeine and 6000-fold less than that of morphine. The O-desmethyl metabolite (ODT or M1) of tramadol has a 200-fold greater affinity than the parent compound for the m-opioid receptor. In addition to its actions on brain opioid receptors tramadol is an inhibitor of serotonin reuptake (+ isomer) and of noradrenaline reuptake (-isomer). Tramadol induces analgesia, but is associated with less respiratory depression than other opioids and has no significant cardiac effects. It has been found to reduce the seizure and sweating thresholds but reduces postoperative shivering. Tramadol has been noted to have some effects on the central nervous system, notably dizziness; sedation; headache and, to a lesser extent, euphoria; central nervous system stimulation (e.g. tremor, agitation, anxiety and hallucinations); dysphoria and seizures. In the 1% of patients who suffered seizures, they were found to be linked to a predisposing factor such as epilepsy, alcohol or drug withdrawal or antidepressant therapy. Toxic effects can be produced directly by the drug and these effects may be exacerbated by the presence of monoamine antidepressant drugs or central nervous system depressant drugs. Overdose has been reported to result in bradycardia, convulsions, respiratory depression and coma.
Animal studies have indicated that tramadol produces little tolerance, has mild withdrawal symptoms and a lower abuse potential than codeine and pentazocine. Nevertheless, together with the rapid increase in the medical use of tramadol worldwide, there have been reports of dependence and abuse, particularly in opioid-dependent individuals. The actions of the drug on brain monoamine systems must also be considered in relation to its abuse potential.
Actual abuse and/or evidence of likelihood of abuse
Of the 103 countries that responded to the WHO Questionnaire, 88 indicated the medical use of tramadol. Of these, 21 reported some abuse and illicit traffic. The reported cases of abuse originated primarily from Europe and the United States. Deaths from overdose were reported from France and the United States. In a few of these countries, abuse of tramadol has led to regulatory actions such as temporary suspension of marketing registration or the use of special prescription forms. However, the assessment of its abuse liability is made difficult by the scarcity of quantitative data and considerable differences in the experiences of individual countries. In Germany where the drug was developed and has been on the market for 25 years without additional controls other than prescription requirements, the data from the drug abuse warning system suggest that tramadol has lower abuse liability than buprenorphine and pentazocine. The data from the drug abuse warning network of the USA, on the other hand, suggest that its abuse potential may be roughly comparable to that of codeine or dextropropoxyphene in the USA. The regulatory authorities in the USA required that the sponsor of tramadol set up an independent group of scientists to conduct post-marketing studies of abuse of and dependence on tramadol. These studies found that the rate of abuse in the year following the introduction of tramadol to the market was 2-3 cases per 100 000 patients. Subsequently, this rate declined to one case per 100 000. The adverse drug reaction reports related to abuse of tramadol collected by the international drug monitoring programme indicate larger numbers of case reports of abuse, dependence and withdrawal syndrome for tramadol than for any other analgesic, except butorphanol, which ranks first in the list of drugs for which “drug dependence” has been reported. Many of these reports originated from the USA, where the consumption of tramadol has been increasing rapidly since it was first marketed in 1995, a situation conducive to higher rates of reporting adverse events.
Tramadol is used as an analgesic agent for the treatment of moderate to severe pain. It became available in Germany in the 1970s and was subsequently marketed in Africa, the Americas and Asia, and is currently used in 104 countries. It is however difficult to judge whether the rapid increase in its medical use reflects the recognition of its therapeutic usefulness. The absence of international control may be a contributing factor.
Pharmacologically, tramadol is more complex than prototypic μ-opioid receptor agonists, but one of its metabolites is a potent μ-opioid receptor agonist. This is consistent with its pattern of abuse which is similar to that of opioids by opioid abusers, as well as its opioid-like analgesic effects. The likelihood of abuse of tramadol appears to vary between countries, depending on the prevalence of opioid dependence, types of marketing strategy and other factors. The information available is not sufficient for the Committee to recommend international control of tramadol, but is adequate to recommend that WHO keep the drug under surveillance.