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By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The FDA recently approved a combination of tramadol and acetaminophen for the short-term management of acute pain. Acetaminophen (APAP), which has long been added to narcotic pain releivers to potentiate their effect, is added to tramadol (Ultram) for the same purpose. The combination, marketed as Ultracet, has a faster onset of action than tramadol alone and longer duration of analgesia than tramadol or acetaminophen alone.
Tramadol/APAP is indicated for the short-term (5 days or less) management of acute pain.1
The recommended dose is 2 tablets every 4-6 hours as needed for pain relief. The maximum dose is 8 tablets per day. The dose should not exceed 2 tablets every 12 hours in patients with impaired renal function (creatinine clearance < 30 mL/min).1 Tramadol should not be used in situations where opioids are contraindicated and should not be used in pregnant women prior to or during labor. Chronic use during pregnancy is also not advised. Tramadol/APAP should be used at a reduced dose and with caution in patients taking other CNS depressants.1
Ultracet is supplied as tablets containing 37.5 mg of tramadol and 325 mg of acetaminophen.
This combination has been reported to provide better pain relief and faster onset of action and a longer duration than equivalent single doses of either APAP or tramadol in oral surgical pain.1 Ultracet is not scheduled.
Tramadol/APAP is only approved for use for 5 days or less.1 Tramadol is less effective in orthopedic surgical pain than dental pain.1 Seizures have been reported in patients taking tramadol and this risk may be increased with concomitant administration of selective serotonin reuptake inhibitors (SSRIs) antidepressants, tricyclic antidepressants (TCAs), or other chemically related drugs (eg, cyclobenzaprine, promethazine), other opioids, MAO inhibitors, neuroleptics, and drugs which may lower seizure thresholds.1 The risk appears to be highest among those aged 25-54 years, with 4 or more prescriptions, and those with a history of alcohol abuse, stroke, or head injury.4 Tramadol has the potential for inducing physical dependence of the opioid type although the incidence has been reported to be less than 1 per 100,000.1,5 This was based on data collected as part of a postmarketing surveillance program. Abstinence syndrome has been reported and dose tapering may be considered.7 Tramadol/APAP may impair mental and physical ability to drive or operate machinery and other drugs with similar effects could enhance these effects.
The intent of combination analgesics is to provide a synergistic action as well as facilitate prescribing. Combination analgesics may also improve compliance by reducing the total number of tablets a patient must take to manage pain. Tramadol is a synthetic, centrally acting analgesic with 2 different mechanisms. These include a opioid mechanism (binding to m-receptor) and a nonopioid mechanism involving reuptake of norepinephrine and serotonin.3 It is less likely to cause respiratory depression, constipation, and dependence than narcotic analgesics. However, tramadol alone is not a high quality analgesic, it has been categorized by the World Health Organization as an analgesic of low quality and no better than codeine/APAP.6 The addition of APAP to tramadol appears to result in synergistic analgesia in mice models and it appears to be addictive in humans.1,2 In oral surgical pain, tramadol/APAP is a little less effective than hydrocodone/APAP on a tablet for tablet basis but more effective than tramadol or APAP alone.1 Ultracet is priced at approximately $0.80 per tablet which is the same as tramadol (50 mg).
Tramadol/APAP provides a combination which appears to be more effective than tramadol or APAP alone in relieving pain. In patients in whom NSAIDs or narcotic analgesic combinations are not appropriate, particularly due to intolerance, tramadol/APAP may offer another option. However, its use is recommended for only 5 days or less.
1. Ultracet Product Information. Ortho-McNeil Pharmaceutical, Inc. August 2001.
2. Raffa RB. J Clin Pharm Ther. 2001;26(4):257-264.
3. Scott LJ, Perry CM. Drugs. 2000;60(1):139-176.
4. Gardner JS, et al. Pharmacotherapy. 2000;20(12): 1423-1431.
5. Cicero TJ, et al. Drug Alcohol Depend. 1999;57(1):7-22.
6. Prescrire Int. 1998;7(33):9-12.
7. Freye E, Levy J. Eur J Pain. 2000;4(3):307-311.
Dr. Chan, Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA, and Dr. Elliott, Chair, Formulary Committee, Northern California Kaiser Permanente, and Assistant. Clinical Professor of Medicine, University of California-San Francisco, are Associate Editors of Internal Medicine Alert.