2-[(Dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol
Recommendation (from TRS)
Substance identification
Tramadol ((1R*,2R*)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexan-1-ol) is marketed as the hydrochloride salt and is available in a variety of pharmaceutical formulations for oral (tablets, capsules), sublingual (drops), intranasal, rectal (suppositories), intravenous, subcutaneous and intramuscular administration. It is also available in combination with acetaminophen (paracetamol). Preparations of tramadol are available as immediate- and extended-release formulations.
WHO review history
Tramadol has been considered for critical review by the ECDD five times: in 1992, 2000, 2002, 2006 and 2014. Tramadol was pre-reviewed at the thirty-ninth meeting of the ECDD in November 2017 and it was recommended that tramadol be subject to a critical review at a subsequent ECDD meeting. The Committee requested the ECDD Secretariat to collect additional data for the critical review, including information on the extent of problems associated with tramadol misuse in countries. Also, the Committee asked for information on the medical use of tramadol, including the extent to which low-income countries, and aid and relief agencies, use and possibly rely on tramadol for provision of analgesia. In response to these requests, the ECDD Secretariat collected data from Member States and relief agencies on the extent of medical use of tramadol, its misuse and on the level of control implemented in countries.
Similarity to known substances and effects on the central nervous system
Tramadol is a weak opioid analgesic that produces opioid-like effects primarily due to its metabolite, O-desmethyltramadol. The analgesic effect of tramadol is also believed to involve its actions on noradrenergic and serotonergic receptor systems. The adverse effects of tramadol are consistent with its dual opioid and non-opioid mechanisms of action and they include dizziness, nausea, constipation and headache. Overdose leads to symptoms such as lethargy, nausea, agitation, hostility, aggression, tachycardia, hypertension and other cardiac complications, renal complications, seizures, respiratory depression and coma. Serotonin syndrome (a group of symptoms associated with high concentrations of the neurotransmitter serotonin that include elevated body temperature, agitation, confusion, enhanced reflexes and tremor and, in some instances, seizures and respiratory arrest) is a potential complication of the use of tramadol in combination with other serotonergic drugs. Tramadol has been detected in a number of postmortem samples. It is often present along with other drugs, including opioids, benzodiazepines and antidepressants, but fatalities have also been reported due to tramadol alone.
Dependence potential
Evidence suggests that the development of physical dependence to tramadol is dose-related, and administration of supra-therapeutic doses leads to a similar dependence profile to that of morphine and other opioids such as oxycodone and methadone. There are reports of considerable numbers of people seeking help for tramadol dependence. Withdrawal symptoms include those typical of opioids such as pain, sweating, diarrhoea and insomnia. There are also symptoms not normally associated with opioid use, which are related to noradrenergic and serotonergic activity, such as hallucinations, paranoia, confusion and sensory abnormalities. Low-dose tramadol used over extended periods is associated with a lower risk of dependence.
Actual abuse and/or evidence of likelihood of abuse
Consistent with its opioid mechanism of action, human brain imaging has shown that tramadol activates brain reward pathways associated with abuse. While tramadol has been reported to produce opioid-like reinforcing effects in controlled settings and in experienced opioid users, these effects may be weaker than those produced by opioids such as morphine. They may also be partially offset by unpleasant effects of tramadol such as sweating, tremor, agitation, anxiety and insomnia.
Abuse, dependence and tramadol overdose have emerged as serious public health concerns in countries across several regions. Epidemiological studies in the past have reported a lower tendency for tramadol misuse when compared to other opioids, but more recent information indicates a growing number of people abusing tramadol, particularly in a number of African and Middle Eastern countries. The sources of tramadol include diverted medicines as well as falsified medicines containing high doses of tramadol. Seizures of illicitly trafficked tramadol, particularly in African countries, have risen dramatically in recent years.
The oral route of administration has been the predominant mode of tramadol abuse as it results in a greater opioid effect than other routes. It is unlikely that when used nonmedically, tramadol is injected to any significant extent. Abuse of tramadol is likely to be influenced by genetic factors such that some people will experience a much stronger opioid effect following tramadol administration than others. The genetic factors are present at different rates in different populations across different parts of the world.
Many countries have placed tramadol under national control.
Therapeutic usefulness
Tramadol is used to treat both acute and chronic pain of moderate to severe intensity. The conditions for which tramadol has been used include osteoarthritis, neuropathic pain, chronic low back pain, cancer pain and postoperative pain. It has also been used for treatment of restless legs syndrome and in opioid withdrawal management. As is the case with abuse potential, the analgesic efficacy and the nature of adverse effects experienced are strongly influenced by genetic factors. Systematic reviews have suggested that the ability of tramadol to control chronic pain such as cancer pain is less than that of strong opioids such as morphine, and its use is associated with a relatively high prevalence of adverse effects.
Tramadol is listed on the national essential medicines lists of many countries across diverse regions, but it is not listed on the WHO EML.
As an opioid analgesic available in generic forms, which is not under international control, tramadol is widely used in many countries where access to other opioids for the management of pain is limited. It is also used extensively by international aid organizations in emergency and crisis situations for the same reasons.
Recommendations
The Committee was concerned by the increasing evidence of tramadol abuse in a number of countries in diverse regions, in particular the widespread abuse of tramadol in many low-to-middle-income countries. Equally concerning was the clear lack of availability of alternative analgesics in a number of countries and in emergency and crisis situations where tramadol is used for treatment of moderate to severe pain. The Committee was strongly of the view that the extent of abuse and evidence of public health risks associated with tramadol warranted consideration of scheduling. However, it recommended that tramadol not be scheduled at this time in order to avoid an adverse impact on access to this medication, especially in countries where tramadol may be the only available opioid analgesic, or in crisis situations where there is little or no access at all to other opioids.
The Committee also strongly urged WHO and its partners to address, as a high priority, the grossly inadequate access to and availability of opioid pain medication in low-income countries. WHO and its partners are also strongly encouraged to update and disseminate WHO pain management guidelines and to support both country-specific capacity-building needs and prevention and treatment initiatives in order to address the tramadol crisis in low-income countries. The Committee also recommended that WHO and its partners support countries in strengthening their regulatory capacity and mechanisms for preventing the supply and use of falsified and substandard tramadol.
■■ Recommendation: The Committee recommended that the WHO Secretariat should continue to keep tramadol under surveillance, col- lect information on the extent of problems associated with tramadol misuse and on its medical use, and that tramadol be considered for review at a future meeting.
ECDD Recommendation
Recommended for surveillance at 33rd ECDD (2002)
Tramadol is used therapeutically in the treatment of acute and chronic pain of moderate to severe intensity. It produces opioid-like effects with adverse effects including respiratory depression, nausea, dizziness, and vomiting. Tramadol is used world-wide and is listed in many medical guidelines for pain treatment. There is some evidence of abuse and several Member States have reported seizures of illicit tramadol. Fatal intoxications are rare and appear to be associated with large overdoses of tramadol and co-ingestion of other drugs (including alcohol). Tramadol was pre-reviewed at the 28th meeting (1992) and the 32nd meeting (2000) of the ECDD. A critical review was undertaken at the 33rd meeting (2002), however, the Committee decided that the information was not sufficient to recommend international control of tramadol, but was adequate to recommend surveillance. Subsequently, tramadol was pre-reviewed again at the 34th meeting (2006), however, the Committee concluded that there was not sufficient evidence to justify a critical review. An update on tramadol was considered at the 36th meeting (2014) and once again the Committee concluded there was insufficient evidence to warrant a critical review. The 41st ECDD was concerned by the increasing evidence of tramadol abuse in a number of countries in diverse regions, in particular the widespread abuse of tramadol in many low-to-middle-income countries. Equally concerning was the clear lack of availability of alternative analgesics in a number of countries and in emergency and crisis situations where tramadol is used for treatment of moderate to severe pain. The 41st ECDD was strongly of the view that the extent of abuse and evidence of public health risks associated with tramadol warranted consideration of scheduling. However, it recommended that tramadol not be scheduled at this time in order to avoid an adverse impact on access to this medication, especially in countries where tramadol may be the only available opioid analgesic, or in crisis situations where there is little or no access at all to other opioids. The 41st ECDD also strongly urged WHO and its partners to address, as a high priority, the grossly inadequate access to and availability of opioid pain medication in low-income countries. WHO and its partners are also strongly encouraged to update and disseminate WHO pain management guidelines and to support both country-specific capacity-building needs and prevention and treatment initiatives in order to address the tramadol crisis in low-income countries. The 41st ECDD also recommended that WHO and its partners support countries in strengthening their regulatory capacity and mechanisms for preventing the supply and use of falsified and substandard tramadol. The 41st ECDD recommended that the WHO Secretariat should continue to keep tramadol under surveillance, collect information on the extent of problems associated with tramadol misuse and on its medical use, and that tramadol be considered for review at a future meeting.