Tramadol Safety Concerns
Tramadol is a widely used centrally acting synthetic opioid analgesic indicated for moderate to moderately severe pain. Tramadol's analgesic activity results from at least two complementary mechanisms of action including binding of μ-opioid receptors and weak inhibition of the reuptake of norepinephrine and serotonin.1-3
In 1995, tramadol was first introduced in the United States under the brand name Ultram and was initially marketed as a safer noncontrolled analgesic with less potential for abuse than opioids. Despite reports of abuse over the years, the use of tramadol has become increasingly common, up 88% from 23.3 million in 2008 to 43.8 million in 2013.2-3 Tramadol has become the second most commonly prescribed narcotic-type analgesic, ranking behind only hydrocodone/acetaminophen products.3
DEA Schedule Changes
In many states, nurse practitioners (NPs) or physicians assistants (PAs) can prescribe only schedule III-IV controlled substances. With limited or no prescriptive authority to prescribe hydrocodone-containing products and other schedule II analgesics, one potential unintended consequence of these scheduling changes is increased prescribing of tramadol, codeine, and NSAIDs in the elderly population who are also the most vulnerable to the risks of these medications.
Additional concerns exist in long term care (LTC) centers where the frailest elderly patients often reside. NPs and PAs are widely used in LTC centers to provide essential care to long term care residents. Because of the limited analgesic choices available to NPs and PAs, along with other DEA requirements that make the prescribing of controlled substances more challenging in LTC nursing centers, there is an increased likelihood of older adults receiving other less appropriate analgesics.
Coordinating Care With Scheduled Narcotics
General Overview of Tramadol Risks
Increased Risk of ED Visits
As older adults are more susceptible to adverse effects of medications in general, it is essential for health care providers to recognize tramadol-associated risk in this population. Older adults are particularly vulnerable, with patients aged 65 and older accounting for approximately one-third (35%) of tramadol-related ED visits involving adverse reactions in 2011. Increased awareness of this risk may assist with the development of more appropriate medication regimens with improved monitoring parameters.7
Risk of Overdosage
Patients taking tramadol should be warned not to exceed the dose recommended by their prescriber and cautioned about the concomitant use of tramadol products and alcohol because of potentially serious CNS additive effects of these agents. Patients should be advised of the additive depressant effects when used with other CNS depressant medications. 1,2,4-7
Seizures have been reported in patients receiving tramadol within the recommended dosage range, even following the first dose. Concomitant use of tramadol increases risk of seizures in patients taking selective serotonin reuptake inhibitors (SSRIs), anorectics, neuroleptics, tricyclics, cyclobenzaprine, promethazine, opioids, monoamine oxidase inhibitors, or any other drugs that lower the seizure threshold (see Table 2). The risk of convulsions may also increase in patients with epilepsy, those with a history of seizures, or in patients with a recognized risk of seizure, such as from head trauma, metabolic disorders, alcohol and drug withdrawal, and CNS infections. Alternative analgesics may be indicated for patients with known seizure risk.1,2,4-7,9
When patients begin taking tramadol or increase the dose, they should be counseled to watch for symptoms of SS, which can be reversed if detected early. SS is most commonly caused by SSRIs. However, other drugs such as opioid analgesics, antibiotics, antimigraine agents, illicit drugs, and over-the-counter drugs alone or in combination can also lead to SS. These drugs can interact with tramadol and can increase the risk of SS. Advise patients to check with the prescriber or pharmacist before taking new prescriptions, over-the-counter medications, or herbal remedies, such as St. John's Wort, nutmeg, or 5-HTP.
PT/INR Prolongation With Warfarin
In a second study published in late 2014, researchers conducted a retrospective analysis of 334,034 patients (28,100 new users of tramadol and 305,924 new users of codeine) of whom 1,105 were hospitalized for hypoglycemia, with 112 patients dying as a result of hypoglycemia. Compared with codeine, tramadol use was associated with a 52% increased risk of hospitalization. Patients appear to be at the greatest risk of hospitalization due to hypoglycemia during the first 30 days of initiating tramadol. Results of the analysis showed a greater than threefold increase in hospitalization for hypoglycemia in those patients who had started taking tramadol within the prior 30 days.13
Although both studies suggest an association between tramadol and hypoglycemia, because they are both observational retrospective studies, the studies do not allow a definitive causal relationship to be made. However, it is appropriate for health care professionals to be aware of this potential and increase monitoring in the elderly and those patients with kidney disease or who are taking medications that can cause hypoglycemia.
— Mark D. Coggins, PharmD, CGP, FASCP, is senior director of pharmacy services for skilled nursing centers operated by Diversicare in eight states, and is a director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.
2. Tramadol (trade names: Ultram, Ultracet). Drug Enforcement Administration, Office of Diversion Control website. http://www.deadiversion.usdoj.gov/drug_chem_info/tramadol.pdf. Updated July 2014.
3. Top 25 medicines by dispensed prescriptions (US). IMS Health website. http://www.imshealth.com/deployedfiles/imshealth/Global/Content/Corporate/Press%20Room/2012_
4. Hydrocodone (trade names: Vicodin, Lortab, Lorcet-HD, Hycodan, Vicoprofen). Drug Enforcement Administration, Office of Diversion Control website. http://www.deadiversion.usdoj.gov/drug_chem_info/hydrocodone.pdf. Updated October 2014.
5. Lipman AG. Analgesic drugs for neuropathic and sympathetically maintained pain. Clin Geriatr Med. 1996;12(3):501-515.
6. Cavalieri TA. Management of pain in older adults. J Am Osteopath Assoc. 2005;105(3 Suppl 1):S12-S17.
7. Bush DM. The CBHSQ report: emergency department visits for adverse reactions involving the pain medication tramadol. http://www.samhsa.gov/data/sites/default/files/report_1965/ShortReport-1965.html. Published May 14, 2015. Accessed May 17, 2015.
8. Ramsay RE, Rowan AJ, Pryor FM. Special considerations in treating the elderly patient with epilepsy. Neurology. 2004;62(5 Suppl 2):S24-S29.
9. Baxter K. Stockley's Drug Interactions [online]. Medicines Complete website. https://www.medicinescomplete.com/mc/stockley/current/login.htm?uri=https%3A%2F%2F
10. Mackay FJ, Dunn NR, Mann RD. Antidepressants and the serotonin syndrome in general practice. Br J Gen Pract. 1999;49(448):871-874.
11. Igbal MM, Basil MJ, Kaplan J, Iqbal MT. Overview of serotonin syndrome. Ann Clin Psychiatry. 2012;24(4):310-318.
12. Bourne C, Gouraud A, Daveluy A, et al. Tramadol and hypoglycaemia: comparison with other step 2 analgesic drugs. Br J Clin Pharmacol. 2013;75(4):1063-1067.
13. Fournier JP, Azoulay L, Yin H, Montastruc JL, Suissa S. Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain. JAMA Intern Med. 2015;175(2):186-193.