Criteria for Outpatient Use Guidelines

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[Developed, November 1995; Revised, December 1996; November 1997; November 1998; December 1999; October 2000; November 2001; October 2002; November 2003; April 2008; January 2011]

Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with [*].

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1.* Dosage

Adults
Tramadol is a centrally acting, opioid-type analgesic that acts as a mu-opioid receptor agonist and a weak inhibitor of serotonin and norepinephrine reuptake.  The immediate-release (IR) formulation is FDA-approved for use in the management of acute or chronic moderate to moderately severe pain in adults.  Tramadol extended-release (ER) is FDA-approved for use in managing chronic moderate to moderately severe pain in patients requiring continuous pain management.  The tramadol/acetaminophen combination is FDA-approved for the acute (< 5 days) management of acute pain.  Following a titration phase, recommended immediate-release (IR) tramadol regimens for pain management include doses of 50 mg to 100 mg administered every 4 to 6 hours as needed.  For tramadol extended-release (ER), the recommended initial dose in tramadol IR-naïve patients is 100 mg once daily, titrated every five days in 100 mg increments until pain relief is achieved.  For those patients already managed on tramadol IR, the 24- hour dose should be calculated and the total daily tramadol ER dose should be rounded down to the closest 100 mg increment. The recommended dose for tramadol in combination with acetaminophen is 2 tablets every 4 to 6 hours as needed for pain relief.  Maximum recommended doses for tramadol alone and in combination with acetaminophen are summarized in Table 1.  Dosages exceeding these recommendations will be reviewed.

Table 1
Maximum Recommended Oral Tramadol Dosages in Adults

DRUG	MAXIMUM RECOMMENDED DOSE
Monotherapy
Tramadol immediate-release (Ultram®) 50 mg tablets	400 mg/day
Tramadol extended-release (Ultram® ER) 100 mg, 200 mg, 300 mg tablets	300 mg/day
Combination Therapy
Tramadol/acetaminophen (Ultracet®) 37.5 mg/325 mg tablets	300 mg/2600 mg per day (8 tablets)

Tramadol dosages exceeding 300 mg per day in elderly patients over 75 years of age are not recommended and will be reviewed.

In patients with a creatinine clearance < 30 ml/min, the recommended dosing interval for tramadol IR is every 12 hours and the maximum recommended tramadol dose is 200 mg per day.  In patients with cirrhosis, the recommended tramadol IR dose is 50 mg every 12 hours.  Tramadol ER should not be administered to patients with a creatinine clearance < 30 ml/min or patients with hepatic impairment.

Pediatrics
Tramadol use in the pediatric population is not recommended as safety and efficacy of tramadol in patients less than 18 years of age have not been established.

2. Duration of Therapy

There is no basis for limiting the duration of tramadol therapy as tramadol is promoted for use in chronic pain (e.g., chronic musculoskeletal pain, cancer pain) as well as acute pain events (e.g., postoperative pain, dental extraction pain). However, cases of tramadol abuse and dependence have been reported, especially in patients with a history of substance abuse. Therefore, tramadol should be administered cautiously, if at all, to patients with a history of drug or alcohol abuse and/or dependence.

The tramadol/acetaminophen combination is indicated for use in the short-term management of acute pain and should be limited to five days or less of use. Patient profiles containing tramadol/acetaminophen prescriptions exceeding this treatment duration will be reviewed.

3.* Duplicative Therapy

Adjunctive administration of multiple tramadol dosage forms may result in significant additive adverse events, including respiratory depression, seizures and serotonin syndrome. Combined administration of multiple tramadol dosage forms is not recommended and will be reviewed.

Opioid analgesics may enhance the sedative effects as well as other central effects of tramadol. Therefore, the use of tramadol in conjunction with opioid analgesics is recommended cautiously. If tramadol is used concomitantly with another agent that acts upon the central nervous system, the tramadol dosage should be reduced.

Use of tramadol in conjunction with sedative/hypnotics in patients over 75 years of age will be reviewed as these patients may be more sensitive to the additive effects of this drug combination.

4.* Drug-Drug Interactions

Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions.

Drug-drug interactions considered clinically relevant for tramadol are summarized in Table 2.  Only those drug-drug interactions identified as clinical significance level 1 or those considered life-threatening which have not yet been classified will be reviewed:

Table 2
Tramadol Drug-Drug Interactions

Target Drug	Interacting Drug	Interaction	Recommendations	Clinical Significance
tramadol	carbamazepine (CBZ)	potential for reduced analgesic effect due to CBZ-associated CYP3A4 enzyme induction; potential for additive CNS depressant effects, increased seizure risk with concurrent therapy	concurrent use not recommended	major (DrugReax) 2-major (CP)
tramadol	CYP inducers (e.g., phenytoin, rifampin)	potential for reduced tramadol analgesic efficacy as tramadol metabolized by CYP3A4, CYP2D6	monitor for reduced analgesic effects; adjust dosages as necessary	moderate (DrugReax) 3-moderate (CP)
tramadol	CYP2D6 inhibitors (e.g., amiodarone, propafenone,  ritonavir)	potential for enhanced tramadol pharmacologic/adverse effects as tramadol metabolized by CYP2D6	monitor for enhanced analgesic effects, increased adverse effects (including seizures); adjust dosages as necessary	moderate (DrugReax) 3-moderate (CP)
tramadol	CYP3A4 inhibitors (e.g., amiodarone, erythromycin,  ritonavir)	potential for enhanced tramadol pharmacologic/adverse effects as tramadol metabolized by CYP3A4	monitor for enhanced analgesic effects, increased adverse effects (including seizures); adjust dosages as necessary	moderate (DrugReax) 3-moderate (CP)
tramadol	MAOIs/MAOI-like compounds (e.g., phenelzine, selegiline, rasagiline, linezolid)	potential for additive effects on serotonin and norepinephrine reuptake inhibition; increased risk for seizures,  hypertensive reactions, serotonin syndrome (e.g., nausea, vomiting, hypertension, hyperthermia, cardiovascular collapse)	concurrent administration or prescribing within 14 days of MAOI discontinuation contraindicated	contraindicated, major (DrugReax) 1-severe, 2-major (CP)
tramadol	neuroleptics (e.g., thioridazine, risperidone)	increased seizure risk (mechanism unknown), and potential for increased CNS, respiratory depression	avoid, if possible, in patients with underlying seizure disorders; otherwise, use cautiously together	major (DrugReax) 2-major (CP)
tramadol	opioid analgesics	increased seizure risk	avoid, if possible, in patients with underlying seizure disorders; otherwise, use cautiously together	2-major (CP)
tramadol	serotonergic drugs (e.g., SSRIs/SNRIs, milnacipran)	increased seizure risk, increased risk of serotonin syndrome (e.g., nausea/vomiting, hypertension, hyperthermia, cardiovascular collapse) due to additive increases in serotonin concentrations	avoid, if possible, in patients with underlying seizure disorders; otherwise, use cautiously together	major (DrugReax) 2-major (CP) 1 (DIF)
tramadol	TCAs (e.g., imipramine, cyclobenzaprine)	increased seizure risk (TCAs lower seizure threshold), increased risk of serotonin syndrome (e.g., nausea/vomiting, hypertension, hyperthermia, cardiovascular collapse) as both compounds inhibit serotonin/norepinephrine reuptake	avoid, if possible, in patients with underlying seizure disorders; otherwise, use cautiously together	major (DrugReax) 3-moderate (CP) 2 (DIF)
tramadol	warfarin	increased prothrombin time with increased bleeding risk; mechanism unknown	closely monitor for INR changes, bleeding; adjust doses as necessary	moderate (DrugReax) 2-major (CP) 2 (DIF)

References

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2. Tramadol tablets (Ultram®) Package Insert.  Pricara/Ortho-McNeil Janssen Pharmaceuticals, September 2009.
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Prepared by: Drug Information Service, The University of Texas Health Science Center at San Antonio, and the College of Pharmacy, The University of Texas at Austin.