Tramadol

DEFINITION: Tramadol is an opioid analgesic with morphine-like properties. It works as a central nervous system depressant and an analgesic.

• ALSO KNOWN AS: Ultram

• STATUS: Legal by prescription in the United States and worldwide
• CLASSIFICATION: Nonscheduled status, but US state laws vary
• SOURCE: Synthetic analog of codeine with no natural sources
• TRANSMISSION ROUTE: Ingested orally, inhaled, or injected

History of Use

Tramadol was first synthesized in 1962 by the German pharmaceutical company Grünenthal. Tramadol has been in clinical use in Germany since 1977. Originally marketed as a safe painkiller with a low risk of abuse, tramadol became the most prescribed opioid on the European market. It was introduced to the prescription drug market in the United States in 1995 as Ultram, a nontraditional, centrally acting analgesic. Tramadol initially had a non-scheduled status because it was believed it had a low potential for abuse. It has since become a controlled substance.

Tramadol produces pleasurable sensations and relaxation without increased drowsiness, enabling people to remain productive while managing pain. It was once an easily obtainable opiate in the United States. However, it can be habit-forming because of its morphine-like properties. Because of reports of increased tramadol misuse, as of August 18, 2014, the Drug Enforcement Administration (DEA) has classified tramadol as a Schedule IV controlled substance nationwide.

Effects and Potential Risks

Tramadol is a nontraditional, centrally acting opioid analgesic with morphine-like pain-relieving activity. It has a dual mechanism of pain relief because it includes a mixture of enantiomers.

Studies suggest that tramadol activity is mediated through both opioid and non-opioid or monoaminergic mechanisms. It exhibits opioid activity by binding to specific opioid receptors in the brain that decrease pain perception. Monoaminergic activity is displayed by inhibiting the reuptake of norepinephrine and serotonin, neurotransmitters responsible for altering pain response in the brain.

The short-term effects of tramadol include feelings of euphoria, mood elevation, and relaxation. Tramadol is usually well-tolerated but can be associated with negative short-term effects, including nausea, vomiting, constipation, drowsiness, dizziness, vertigo, weakness, and headache.

Long-term use of tramadol can be associated with drug dependence and possible addiction. Tramadol lowers seizure threshold, particularly in high doses, and it can contribute to serotonin syndrome when taken with selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), or other serotonergic drugs. Abruptly stopping tramadol may generate opiate-like withdrawal symptoms such as anxiety, agitation, sweating, abdominal upset, and hallucinations.

Bibliography

Chabot, Sandra. "Tramadol (Ultram, Conzip, Qdolo) - Uses, Side Effects, and More." WebMD, 23 July 2024, www.webmd.com/drugs/2/drug-4398-5239/tramadol-oral/tramadol-oral/details. Accessed 6 Oct. 2025.

Dhesi, Manraj, et al. “Tramadol - Statpearls.” National Center for Biotechnology Information, 20 Feb. 2024, www.ncbi.nlm.nih.gov/books/NBK537060/. Accessed 6 Oct. 2025.

Duehmke, Rudolf Martin, et al. "Tramadol for Neuropathic Pain in Adults." The Cochrane Database of Systematic Reviews, 2017. Cochrane Library, doi.org/10.1002/14651858.CD003726.pub4. Accessed 6 Oct. 2025.

Grond, Stefan, and Armin Sablotzki. "Clinical Pharmacology of Tramadol." Clinical Pharmacokinetics, vol. 43, no. 13, 2004, pp. 879-923.

Raffa, Robert B. "Basic Pharmacology Relevant to Drug Abuse Assessment: Tramadol as Example." Journal of Clinical Pharmacy and Therapeutics, vol. 33, no. 2, 2008, pp. 101-108.

Senay, Edward C., et al. "Physical Dependence on Ultram (Tramadol Hydrochloride): Both Opioid-Like and Atypical Withdrawal Symptoms Occur." Drug and Alcohol Dependence, vol. 69, no. 3, 2003, pp. 233-241.