The many reasons to avoid the “light” opioid option in the ED.
Introduction: For many years, tramadol has been used to treat acute and chronic pain. It is often considered a “light” opioid option, and has enjoyed a reputation of being a “safer” opioid in terms of adverse effects and abuse potential. In recent years, however, numerous reports have emerged showing the potentially harmful effects of tramadol, which have tainted its reputation as a “safer” opioid option. Despite ever-increasing evidence of potential harm, in 2019, tramadol still remains one of the top 40 drugs prescribed in the United States, with retail pharmacy database reports of over 20 million scripts annually. We will review the evidence to date, and hopefully will help you think twice before you sign off on a script for it on your next shift.
Notable history: Tramadol was originally released in Germany in 1977, and was FDA-approved in the US in 1995 as a mixed, synthetic, centrally-acting opioid analgesic to treat moderate to severe pain. It is available in immediate and extended release formulations via several generic manufacturers. It is commonly used alone or in combination with non-opioid analgesics and NSAIDs for a wide variety of pain types, including: musculoskeletal, dental, postoperative, cancer, neuropathic and osteoarthritis, among others.
How it works: Tramadol is a biochemically messy agent. It is actually a serotonin norepinephrine reuptake inhibitor (SNRI), with a chemical structure strikingly similar to other SNRI agents like venlafaxine. The SNRI effects on analgesia are not fully understood, but thought to be due to enhancement of monoamine reuptake, which leads to inhibitory effects on pain transmission in the spinal cord. Its opioid analgesic effects are mediated almost completely by a metabolite, O-desmethyltramadol, known as M1, which is a mu opioid receptor agonist. M1 has 200 to 300 times stronger activity at mu receptors compared to tramadol itself.
The conversion of tramadol to M1 is dependent on hepatic metabolism via the CYP2D6 pathway. Further complicating matters, CYP2D6 is highly variable from person to person because of genetic polymorphisms, and it is also heavily affected by numerous other drugs. Similarly to codeine, there are both slow and fast metabolizers of tramadol. So when some patients say “tramadol didn’t work for my pain,” they may actually be telling the pharmaco-genetic truth.
One study showed that CYP2D6 poor metabolizers (10% of Caucasians) had a four-fold increase in non-response rates compared with other genotypes. It also showed that co-medication with other CYP2D6 inhibitors (including common co-prescriptions such as fluoxetine, paroxetine, bupropion, duloxetine, celecoxib) significantly decreased M1 concentrations, resulting in poor efficacy for analgesic effects. On the other end of the spectrum, ultra-rapid metabolizers (2-10% of the population) are at significantly increased risk for side effects of M1’s opioid effects such as nausea, sedation, respiratory depression and unintentional overdose.
Patients with hepatic dysfunction are at significant risk of accumulation and toxicity.[2,3] Over 30% of tramadol is excreted unchanged in the urine, which means patients with CKD are at higher risk for toxicity and adverse effects. Did we mention that tramadol is a bio-pharmacological mess? In summary, predicting the degree of SNRI vs. opioid activity in any given patient is a bit like rolling the dice.
Cause for Pause: In addition to the theoretical concerns surrounding tramadol use based in its pharmacology, the real world evidence for concern continues to build. Tramadol is associated with new-onset seizures in patients taking both normal and excessive amounts of tramadol. Seizures are generally tonic-clonic, occur within 24 hours of initiation, and are more common in patients taking other serotonergic agents, alcohol or medications that reduce the seizure threshold like bupropion.[4,5] Tramadol can also trigger serotonin syndrome when combined with other serotonergic agents, including SSRIs, SNRIs, TCAs, MAOIs (including antibiotics like linezolid) and triptans. In one case-control study, tramadol was associated with hypoglycemia in half of patients with DM1, and nearly 20% of patients with DM2. [6,7] Tramadol was also recently associated with higher all-cause mortality within one year of prescription among patients 50 years and older with osteoarthritis, compared with common NSAIDs.
So not only is it a biochemical mess, but it has a bunch of side effects. Finally, it also has high abuse potential. Due to widespread potential for abuse, misuse, and diversion, tramadol is now a classified as a controlled substance in all 50 states. Long-term use of tramadol can result in physiological and psychological dependency, and abrupt discontinuation will precipitate a mixed withdrawal syndrome with characteristics of both opioid and SNRI withdrawal such as nausea, vomiting, sweating, tremors, hallucinations, paranoia and anxiety. Naloxone partially reverses tramadol overdose, but may be associated with increased risk for seizures. According to a 2015 report from the Drug Abuse Warning Network (DAWN), there are over 50,000 annual ED visits in the US related to tramadol use, with over half of those due to adverse effects.
Special Populations: Life threatening respiratory depression can occur if tramadol is used in children and adolescents, and overdose in children is potentially fatal. Tramadol is contraindicated in pregnancy, and is associated with neonatal abstinence syndrome. Tramadol has been added to the Beers List and is not recommended for use in elderly patients. As with many medications, elderly patients are more prone to all adverse effects, particularly constipation and confusion.
Summary: Though tramadol may provide analgesic efficacy for some patients genetically gifted with the right metabolism, the risk of potential adverse effects is high. Tramadol should be avoided in patients with concomitant use of serotonergic agents, TCAs, MAOIs, and sedatives, or who have seizure disorders, diabetes, CKD, hepatic dysfunction, as well as the elderly, pregnant women and children. Significant caution and close monitoring should be used in older patients with OA, history of substance misuse or abuse, and severe asthma or COPD. In other words, tramadol can mess up your biochemistry, has high abuse potential, myriad side effects, variable metabolism based on genetic polymorphisms, and a list of contra-indicated patients longer than a CVS receipt. So be very cautious when you prescribe it or just tramadon’t!
- Medical Expenditure Panel Survey (MEPS) 2006-2016. Agency for Healthcare Research and Quality (AHRQ), Rockville, MD. ClinCalc DrugStats Database version 19.1
- Gong L, Stamer U, Tzvetkov M, et al. PharmGKB summary: tramadol pathway. Phamacogenet Genomics. 2014 July:24(7):374-80. doi:10.1097/FPC.000000000000057.
- Stamer UM, Musshoff F, Kobilay M, et al. Concentration of tramadol and O-desmethyltramadol enantiomers in different CYP2D6 genotypes. Clin Pharmacology and Therapeutics. 2007; 82:41-47. doi:10.1038/sj.clpt.6100152.
- Boyd IW. Tramadol and new-onset seizures. Med J Aust 2005; 182 (11):595-6. doi:10.5694/j.1326-5377.2005.tb06556
- Bostani R, Derakhshan S. Tramadol induced seizure: a 3 year study. Caspian J Intern Med. 2012:3(3):484-887.
- Fournier J, Azoulay L, Yin H, et al. Tramadol Use and the Risk of Hospitalization for Hypoglycemia in Patients With Noncancer Pain. JAMA Intern Med. 2015;175(2):186-193. doi:10.1001/jamainternmed.2014.6512
- Golightly LK, Simendinger BA, Barber GR, et al. Hypoglycemic effects of tramadol analgesia in hospitalized patients: a case-control study. Journal of Diabetes & Metabolic Disorders. 2017;16:30. doi: 0.1186/s40200-017-0311-9.
- Zeng C, Dubreuil M, LaRochelle M, et al. Association of tramadol with all-cause mortality among patients with osteoarthritis. JAMA. 2019; 321(10):969-982. doi:10.1001/jama.2019.1347.
- Bush DM. Emergency Department Visits for Adverse Reactions Involving the Pain Medication Tramadol. 2015 May 14. In: The CBHSQ Report. Rockville (MD): Substance Abuse and Mental Health Services Administration (US); 2013. Accessed Dec. 11, 2018 at https://misuse.ncbi.nlm.nih.gov/error/abuse.shtml