July/August 2015

Tramadol Safety Concerns
By Mark D. Coggins, PharmD, CGP, FASCP
Today's Geriatric Medicine
Vol. 8 No. 4 P. 6

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 August 2014, after nearly two decades of tramadol use in the United States, the Drug Enforcement Agency (DEA) officially made all tramadol-containing products schedule IV controlled substances.2 In October 2014, the DEA took additional steps to help curb prescription drug abuse by rescheduling all hydrocodone-containing products as schedule II controlled substances.4 As a result, the number of oral nonschedule II analgesics available is limited to tramadol and codeine-containing products. 

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
Improved coordination among health care providers including hospitals, nursing centers, and pharmacies can help ensure patients receive the most appropriate pain medication in a more timely manner and with less potential for negative outcomes. Prescribers discharging patients from hospitals and emergency departments (EDs) should take steps to provide controlled substance prescriptions at the time of hospital discharge or release from the ED. Hospital discharge planners and nursing home admission coordinators should work closely together proactively to ensure controlled substance prescriptions are available when a patient is admitted to a nursing center so the prescription can be sent to the pharmacy provider at the time of admission to prevent unnecessary delays in receiving these medications from the pharmacy. Following a patient's admission, prescribers, nurses, and pharmacists should implement processes to routinely evaluate when controlled substance supplies will be depleted so that prescriptions for these medications are on hand and sent to the pharmacy before the last dose is used. When new orders or emergency controlled substance orders are written, nurses should remind prescribers of the need for a prescription by the pharmacy. 

General Overview of Tramadol Risks
In addition to abuse and diversion concerns, additional concerns include the risk of overdose, serotonin syndrome, drug interactions, seizures, and hypoglycemia. To minimize adverse events, prescribe the lowest dose of tramadol that is beneficial for each individual patient (see Table 1). Adverse events may occur as soon as following the first dose at the recommended dosage range, as well as at higher doses. Tramadol's side effects can include nausea, vomiting, constipation, drowsiness, dry mouth, perspiration, dizziness, tremor, confusion, hallucination, blood pressure instability, and seizures. Side effects are most likely to occur during the first seven days of therapy or following dose changes.5,6

Increased Risk of ED Visits
While tramadol can be used safely, significant adverse reactions involving this drug do occur and sometimes result in admission to the hospital. In 2011, there were an estimated 54,397 ED visits involving tramadol, with 50% or 27,421 being attributed to adverse reactions. The number of tramadol-related ED visits involving adverse reactions increased 145% from 10,091 visits in 2005 to 25,884 visits in 2009, while remaining relatively stable in 2010 (25,887 visits) and 2011 (27,421 visits).7

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
Tramadol can cause central nervous system (CNS) depression, respiratory depression, and death. Some deaths have occurred as a consequence of the accidental ingestion of excessive quantities of tramadol alone or in combination with other drugs. It is advised that because of its depressant effects, tramadol should be prescribed with caution and in reduced dosage in those patients whose medical condition requires the concomitant administration of sedatives, tranquilizers, muscle relaxants, antidepressants, or other CNS depressant drugs.1,2,4-7

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

Withdrawal Symptoms
Withdrawal symptoms may occur if tramadol is discontinued abruptly. Symptoms may include anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and, rarely, hallucination. Clinical experience suggests that tapering the dose may relieve withdrawal symptoms.

Seizures
Older adults are at increased risk of seizures with nearly 25% of new seizures occurring in patients aged 65 or older. The increase is often due to changes in the brain caused by stroke, heart disease, Alzheimer's disease, and brain tumors. Additionally, older adults are also susceptible to the effects of medications in general, including drug-induced seizures.8

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

Serotonin Syndrome
Serotonin syndrome (SS) symptoms can range from mild to severe and may be nonspecific. Diagnostic criteria vary, and some clinicians are unfamiliar with the condition. Further complicating the identification of SS is the suggestion that more than 85% of physicians are unfamiliar with the diagnosis or treatment of SS or the drugs or drug combinations that are potentially involved.10 Health care professionals should be aware of this syndrome so they can promptly recognize the symptoms (eg, fast heart rate, high blood pressure, dilated pupils, overreactive reflexes, and/or elevated body temperature) and begin treatment immediately. Patients' medications should be reviewed closely to evaluate for other medications that may increase serotonin and cause SS (see Table 3).7,10,11

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
Prolongation of the international normalized ratio (INR) and prothrombin time and extensive ecchymosis have been reported in patients receiving both tramadol and warfarin. INR may be increased up to threefold. Recommend checking INR three days after starting or increasing/decreasing doses of tramadol. Advise patients to watch for signs of bleeding.9

Hypoglycemia
A 2012 study used the French Pharmacovigilance Database to assess the risk of hypoglycemia with tramadol. Researchers excluded from the data those cases with insufficient data, unconfirmed hypoglycemia, blood glucose levels over 70.2 mg/dL, exposure to selected drugs, or other potential causes of hypoglycemia. Patients taking tramadol and experiencing hypoglycemia were found to have an average blood glucose level of 45 mg/dL. Most patients experienced mild to moderate signs of hypoglycemia; however, approximately 30% experienced severe neurological symptoms such as coma or convulsions. Most cases of hypoglycemia occurred within 10 days of starting tramadol therapy, with the median occurrence at five days. While the majority of patients were elderly and had at least one risk factor such as diabetes or renal insufficiency, hypoglycemia also occurred in nondiabetics without other risk factors.12

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.

References
1. Ultram C IV (tramadol hydrochloride) tablets: full prescribing information. Janssen Pharmaceuticals website. http://www.janssenpharmaceuticalsinc.com/assets/ultram.pdf. Updated July 2014.

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_
U.S/Top_25_Medicines_Dispensed_Prescriptions_U.S..pdf. Updated March 22, 2013. Accessed May 15, 2015.

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
www.medicinescomplete.com%2Fmc%2Fstockley%2Fcurrent%2Findex.htm. London: Pharmaceutical Press. Accessed May 19, 2015.

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.