RATIONALE FOR INCLUSION IN PA PROGRAM Background Tramadol is a centrally acting synthetic opioid analgesic used to treat moderate to moderately severe chronic pain in adults. Along from analgesia, tramadol may produce symptoms including dizziness, somnolence, nausea, constipation, sweating and pruritus similar to opioids. Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin, as have some other opioid analgesics. Like with other opioids, all patients require monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction (1). Regulatory Status FDA-approved indications: Ultram (tramadol) is indicated for the management of moderate to moderately severe pain in adults (1). Ultram ER and Conzip are opioid agonists indicated for the management of moderate to moderately severe chronic pain in adults who require around-theclock treatment of their pain for an extended period of time (2-3). Ultracet is indicated for the shortterm (five days or less) management of acute pain (4). The development of a potentially life-threatening serotonin syndrome may occur with the use of tramadol products, including Ultram and Conzip, particularly with concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs, and SRAs (triptans);with drugs which impair metabolism of serotonin (including MAOIs); and with drugs which impair metabolism of tramadol (CYP2D6 and CYP3A4 inhibitors). This may occur with the recommended dose (1-3). Possible illegal or illicit use should be considered when prescribing or dispensing Ultram in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Misuse or abuse poses a significant risk to the patient that could result in overdose and death. Tramadol should be used in caution with patients with respiratory depression, head trauma, and when used in conjunction with alcohol or other drugs that cause central nervous system depression (1-3). Ultram has a maximum dose of 400mg per day due to increased risk of adverse side effects. Ultracet, Ultram ER and Conzip have a maximum daily dose 300mg. Acute overdose may induce miosis, respiratory depression, seizures, hypotonicity, and acidosis. Chronic side effects include fatigue, dizziness, vertigo, headache, visual disorders, nausea, vomiting, sweating, dry mouth,
constipation, premature heartbeats, euphoria, dysphoria, and hallucinations Seizures have been reported in patients receiving tramadol. Studies have shown Tramadol-induced seizure is dose dependent (5). Ultracet, a combination of tramadol and acetaminophen, has a boxed warning regarding acetaminophen use in excess of 4,000 mg per day. Acetaminophen has been associated with acute liver failure, at times resulting in liver transplant and death. Ultram should not be used concomitantly with other acetaminophen-containing products (4). The safety and efficacy of Ultram ER and Conzip in patients under 18 years of age have not been established (2-3). The safety and efficacy of Ultram and Ultracet in patients under 16 years of age have not been established (1). CDC guidelines find that concurrent use of benzodiazepines and opioids might put patients at greater risk for potentially fatal overdose. Three studies of fatal overdose deaths found evidence of concurrent benzodiazepine use in 31% 61% of decedents (6) CDC guidelines finds that given uncertain benefits and substantial risks that opioids should not be considered first-line or routine therapy for chronic pain (i.e., pain continuing or expected to continue longer than 3 months or past the time of normal tissue healing) outside of active cancer, palliative, and end-of-life care (6). FDA warns that opioids can interact with antidepressants and migraine medicines to cause a serious central nervous system reaction called serotonin syndrome, in which high levels of the chemical serotonin build up in the brain and cause toxicity (see Appendix 1 for list of drugs) (7). The FDA is restricting the use of tramadol in children. Tramadol carries serious risks, including slowed or difficult breathing and death, which appear to be a greater risk in children younger than 12 years, and should not be used in these children (8). Tramadol criteria was created with dosing above FDA limits in order to help existing patients that have been taking doses above the FDA limits to safely taper down their doses to the FDA appropriate levels. This will allow physicians to time to work with their patients in creating a custom
taper that is safe and provides adequate pain control. Summary Tramadol is a centrally acting synthetic opioid analgesic used to treat moderate to moderately severe chronic pain in adults. Concomitant use of serotonergic drugs such as SSRIs, SNRIs, TCAs, MAOIs, and SRAs (triptans) with tramadol may precipitate a potentially life-threatening condition called serotonin syndrome. The safety and efficacy of Ultram ER; Conzip in patients under 18 years of age have not been established (1,2). The safety and efficacy of Ultram in patients under 16 years of age has not been established. Ultracet is approved for short term use only. As with other opioids, all patients require monitoring for signs of abuse and addiction, as use of opioid analgesic products carries the risk of addiction even with appropriate medical care (1). Prior approval is required to ensure the safe, clinically appropriate and cost effective use of Ultram, Ultram ER, and Conzip while maintaining optimal therapeutic outcomes. References 1. Ultram [package insert].guarabo, Puerto Rico: Janssen Ortho, LLC; July 2014. 2. Ultram ER [package insert]. Titusville, New Jersey: Janssen Pharmaceuticals, Inc.; August 2014. 3. Conzip [package insert]. Sayreville, New Jersey: Vertical Pharmaceuticals LLC. July 2014. 4. Ultracet [package insert]. Titusville, New Jersey: Janssen Pharmaceuticals, Inc.; July 2014. 5. Boostani R, Derakhshan S, Tramadol induced seizure: 3 year study. Caspian Journal of Internal Medicine. 2012; 3(3): 484-487. 6. Dowell D, Haegerich T, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain. CDC Guidelines 2016. 7. FDA Safety Release. FDA Drug Safety Communication: FDA warns about several safety issues with opioid pain medicines; requires label changes. March 22, 2016. 8. FDA Safety Release. FDA Drug Safety Communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. April 20, 2017.
Appendix 1 - List of Serotonergic Medications Selective Serotonin Reuptake Inhibitors (SSRIs) paroxetine Paxil, Paxil CR, Pexeva, Brisdelle fluvoxamine Luvox, Luvox CR fluoxetine Prozac, Prozac Weekly, Sarafem, Selfemra, Symbyax sertraline Zoloft citalopram Celexa escitalopram Lexapro Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) venlafaxine Effexor XR desvenlafaxine Pristiq, Khedezla duloxetine Cymbalta milnacipran Savella Tricyclic Antidepressants (TCAs) amitriptyline No brand name currently marketed desipramine Norpramin clomipramine Anafranil imipramine Tofranil, Tofranil PM nortriptyline Pamelor, Aventyl protriptyline Vivactil doxepin Zonalon, Silenor trimipramine Surmontil Monoamine Oxidase Inhibitors (MAOIs) isocarboxazid Marplan phenelzine Nardil selegiline Emsam, Eldepryl, Zelapar tranylcypromine Parnate
Other Psychiatric Medicines amoxapine No brand name currently marketed maprotiline No brand name currently marketed nefazodone No brand name currently marketed trazodone Oleptro buspirone No brand name currently marketed vilazodone Viibryd mirtazapine Remeron, Remeron Soltab llthium Lithobid Migraine Medicines almotriptan Axert frovatriptan Frova naratriptan Amerge rizatriptan Maxalt, Maxalt-MLT sumatriptan Imitrex, Imitrex Statdose, Alsuma, Sumavel Dosepro, Zecuity, Treximet zolmitriptan Zomig, Zomig-ZMT Antiemetics ondansetron granisetron dolasetron palonosetron Zofran, Zofran ODT, Zuplenz Kytril, Sancuso Anzemet Aloxi Other Serotonergic Medicines dextromethorphan linezolid cyclobenzaprine methylene blue St. John s wort tryptophan Bromfed-DM, Delsym, Mucinex DM, Nuedexta Zyvox Amrix