Monday, May 4, 2015

Three Reasons Not to Prescribe Tramadol

Tramadol is a commonly prescribed analgesic that is used to treat a wide variety of painful conditions. Through a somewhat unique mechanism of action, tramadol acts as a mu-opioid receptor agonist and serves as an antagonist to serotonin and norepinephrine receptors. When compared to traditional opioids, tramadol, and its active metabolite M1 (O-desmethyltramadol) bind the mu-opioid receptor with 10 times less affinity than codeine and approximately 100 times less affinity than morphine. While the weak agonist effect of tramadol is thought to provide some pain relief, the inhibition of serotonin and norepinephrine reuptake is thought to provide added analgesia while limiting some of the known adverse effects associated with traditional opioids.


Tramadol has been marketed as a novel analgesic that offers pain relief comparable to opioids without the associated risks of abuse or dependency. As its use has increased, there is emerging data to suggest that tramadol is not a medication that should be routinely used in the emergency department. From questionable efficacy, risk of dependency/abuse, to a somewhat unique risk of complications, there are three major reasons why providers should be careful when using tramadol.

1 - It May Not Work
To date, there is very limited data in terms of the efficacy of tramadol compared to placebo when used in the emergency department. Previous data from a variety of non-emergent settings suggests that tramadol may provide better pain relief than pure placebo. In a study of patients with chronic back pain, Schnitzer et al. reported lower pain scores in patients who received tramadol when compared to those who were given placebo [1].

There is little evidence to suggest that tramadol provides better pain relief than acetaminophen or ibuprofen. In a prospective study of patients with acute abdominal pain, patients were randomized to receive either tramadol, acetaminophen (paracetamol) or placebo. At 20 and 40 minutes intervals, patients who received tramadol or acetaminophen reported a significant decrease in pain scores when compared to patients in the placebo group. The authors found no significant differences in pain scores when tramadol was compared to acetaminophen[2]. Schmeider et al. reported that tramadol provided less pain relief when compared to non-steroidal anti-inflammatories when given to patients with acute biliary colic [3].

Tramadol does not appear to match the analgesic properties of traditional opioids. In prospective study of patients presenting to the ED with acute musculoskeletal pain, patients who received tramadol reported higher pain scores across a range of time intervals when compared to patients who were given a combination product containing hydrocodone and acetaminophen [4]. Hewitt et al. reported that both tramadol-acetaminophen and hydrocodone-acetaminophen combination products performed similarly when use to treat pain from acute ankle sprains [5]. As these authors used a combination of tramadol and acetaminophen, it is unclear how much of pain relief was provided by the combination of these two agents.

Overall there is very little evidence that tramadol is more efficacious than any other commonly available analgesics. In a 2005 review, Sachs et al. examined various oral analgesics, concluding that due to inferior efficacy and an unfavorable side effect profile, tramadol should not be used as a first line agent in the treatment of acute pain [6].

2 - It May Hurt Our Patients
There are several significant potential risks associated with the use of tramadol.

Risk of Erratic Metabolism
Tramadol’s active metabolite, M1, is created after tramadol is metabolized by the CYP2D6 enzyme [7]. As with other analgesics such as codeine, a subset of the population suffers from abnormal activity of this enzyme and is at an increased risk of adverse event when taking tramadol. For patients who have reduced CYP2D6 activity they will generate less of the active metabolite which may result in decreased analgesia. For the subset of patients who exhibit “ultra-rapid” metabolism they may be exposed to a significant increase in tramadol’s opioid-like effects and run the risk of overdose.

Risk of Seizure
Tramadol appears to pose an increased risk of seizure. While multiple analgesics are reported to lower a patient’s seizure threshold, there is emerging data to suggest that this risk may pose an even heightened risk. In a study of patients who experienced “new-onset seizures” Labate et al. reported that 8.2% of cases occurred after exposure to tramadol[8]. The risk of seizure associated with tramadol use was discussed recently in a recent post on Emergency Medicine PharmD by Frank Diaz, PharmD [9].

Risk of Hypoglycemia
Recent studies have suggest that tramadol may result in an increased rate of hypoglycemia. In a recent study, Fournier et al. reported that when compared to patients taking codeine, patients who received tramadol had significant increase in the risk of hypoglycemia that required a hospitalization. The relationship between tramadol and hypoglycemia is still somewhat unclear; however, providers should be aware of this association[10].

Risk of Serotonin Syndrome
When abused or used in conjunction with other agents that limit serotonin reuptake, such as selectiveserotonin reuptake inhibitors, tramadol can increase the risk of a patient developing serotonin syndrome. While the exact risk of serotonin syndrome due to tramadol is difficult to pinpoint, cases of serotonin syndrome have been reported involving the use of tramadol and a wide variety of commonly prescribed antidepressants. Providers should use caution when prescribing to patients who are taking other agents that may limit serotonin re-uptake[11].

3 - It Isn’t A “Safe” Opioid
Initially the FDA reported a low risk of dependency or abuse associated with tramadol and allowed the medication to be marketed without being schedule as a controlled substance. In the years since, there is growing evidence its release there is increasing evidence that tramadol may pose a significant risk of abuse, dependency, and withdrawal in a certain subset of patients. In a 2010 letter to healthcare professionals cautioned against using tramadol in patients who are prone to addiction or with a history of suicidal ideation [12][13].  Due in a large part to this emerging risk of abuse, tramadol has been reclassified as a Schedule IV substance by the DEA [14].

Tramadol poses several unique risks when abused, particularly in the setting of an overdose. There is a high rate of neurotoxicity including seizures and lethargy when patients overdose on tramadol that is thought to be due to the blockade of serotonin and norepinephrine re-uptake rather than coming strictly from the opioid agonist activity. Compared to alternative agents, tramadol may cause significant complications after even relatively minor ingestions with reports of significant neurotoxicity occurring after ingestions of as little as 5 times the recommended dose. As only a small portion of these symptoms come from the opioid receptor, traditional antagonists such as naloxone have limited efficacy when used to treat a tramadol overdose [15].

Conclusion
Despite its widespread use, there are significant issues that providers should consider before using tramadol. In terms of efficacy tramadol has not been shown to consistently outperform other available analgesics. In addition, tramadol has a set of potential side effects that make it a less than ideal first line analgesics. Finally tramadol does not appear to be a “safe opioid” as there seem to be significant potential for abuse, dependency, and withdrawal.

Matthew DeLaney, MD, FACEP, FAAEM (@MDeLaneyMD)
Assistant Professor of Emergency Medicine
Assistant Medical Director
University of Alabama at Birmingham

References: 

  1. Schnitzer TJ, Gray WL, Paster RZ, et al. Efficacy of tramadol in treatment of chronic low back pain. J Rheumatol. 2000 Mar;27(3):772-8. 
  2. Oguzturk H, Ozgur D, Turtay MG, et al. Tramadol or paracetamol do not effect the diagnostic accuracy of acute abdominal pain with significant pain relief - a prospective, randomized, placebo controlled double blind study. Eur Rev Med Pharmacol Sci. 2012 Dec;16(14):1983-8. 
  3. Schmieder G, Stankov G, Zerle G, et al. Observer-blind study with metamizole versus tramadol and butylscopolamine in acute biliary colic pain. Arzneimittelforschung. 1993 Nov;43(11):1216-21. 
  4. Turturro MA, Paris PM, Larkin GL. Tramadol versus hydrocodone-acetaminophen in acute musculoskeletal pain: a randomized, double-blind clinical trial. Ann Emerg Med. 1998 Aug;32(2):139-43. 
  5. Hewitt DJ, Todd KH, Xiang J, et al.; CAPSS-216 Study Investigators. Tramadol/acetaminophen or hydrocodone/acetaminophen for the treatment of ankle sprain: a randomized, placebo-controlled trial. Ann Emerg Med. 2007 Apr;49(4):468-80, 480.e1-2. 
  6. Sachs CJ. Oral analgesics for acute nonspecific pain. Am Fam Physician. 2005;71:913-8.
  7. Leppert W. CYP2D6 in the metabolism of opioids for mild to moderate pain. Pharmacology. 2011;87(5-6):274-85. 
  8. Labate A, Newton MR, Vernon GM, et al.. Tramadol and new-onset seizures. Med J Aust.2005;182:42-44. 
  9. Diaz F. Seizure Risk Associated with Tramadol Use. Emergency Medicine PharmD. 11 September 2014. Available at: http://empharmd.blogspot.com/2014/09/seizure-risk-associated-with-tramadol.html 
  10. Fournier JP, Azoulay L, Yin H, et al. Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain. JAMA Intern Med. 2015 Feb;175(2):186-93.
  11. Sansone RA, Sansone LA. Tramadol: seizures, serotonin syndrome, and coadministered antidepressants. Psychiatry (Edgmont). 2009 Apr;6(4):17-21. 
  12. Tramadol: Important Drug Warnings. Ortho-McNeil-Janssen Pharmaceuticals, Inc.; March 2010. Available at: http://www.fda.gov/downloads/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/UCM213265.pdf
  13. Senay EC, Adams EH, Geller A, et al. Physical dependence on Ultram® (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur. Drug Alcohol Depend 2003;69:233-4. 
  14. Awad NI. The New Scheduling of Tramadol: A Step in the Right Direction. 3 July 2014. Available at: http://empharmd.blogspot.com/2014/07/the-new-classification-of-tramadol-step.html 
  15. Spiller HA, Gorman SE, Villalobos D, et al. Prospective multicenter evaluation of tramadol exposure. J Toxicol Clin Toxicol. 1997;35:361-364.