1. Dosage

Tramadol has a nationwide classification as a Schedule IV controlled substance as of August 18, 2014. Key factors contributing to this decision include its potential for abuse and dependence, as well as its link to emergency room visits and deaths related to overdoses¹.

1.1. 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^2-4. Tramadol extended-release (ER) is FDA-approved for use in managing chronic moderate to moderately severe pain in patients requiring continuous pain management^2,3,5. The tramadol/acetaminophen combination is FDA-approved for the acute (less than 5 days) management of acute pain^2,3,6. Following a titration phase, recommended IR tramadol regimens for pain management include doses of 50 mg to 100 mg administered every 4 to 6 hours as needed. For tramadol 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^2-6. Maximum recommended doses for tramadol alone and in combination with acetaminophen are summarized in Tables 1 and 2. Dosages exceeding these recommendations will be reviewed.

Table 1: Maximum Recommended Adult Oral Tramadol Dosages: Monotherapy^2-5
Drug Name	Dosage Forms/Strengths	Maximum Recommended Dose
tramadol immediate-release (Ultram®, generics)	50 mg tablets	400 mg/day, in divided doses every 4-6 hours elderly*: 300 mg/day, in divided doses every 4-6 hours
tramadol extended-release (generics)	100 mg, 200 mg, 300 mg tablets	300 mg/day in single daily doses
tramadol extended-release (ConZip®, generics)	100 mg, 150 mg, 200 mg, 300 mg capsules	300 mg/day in single daily doses

Legend

* = greater than 75 years of age

Table 2: Maximum Recommended Adult Oral Tramadol Dosages: Combination Therapy^2,3,6
Drug Name	Dosage Forms/Strengths	Maximum Recommended Dose
tramadol/acetaminophen (Ultracet®, generics)	37.5 mg/325 mg tablets	300 mg/2600 mg per day (8 tablets per day), in divided doses every 4-6 hours

1.1.1. Elderly Patients

Tramadol dosages exceeding 300 mg per day in elderly patients over 75 years of age are not recommended and will be reviewed. In controlled clinical trials, treatment-limiting adverse events were higher in patients over 75 years of age compared to those less than 65 years of age^2-7.

1.1.2. Dosing in Renal and Hepatic Impairment

In patients with a creatinine clearance less than 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 given to patients with a creatinine clearance less than 30 mL/min or those with severe hepatic impairment. The tramadol/acetaminophen combination should be dosed as 2 tablets every 12 hours in patients with a creatinine clearance less than 30 mL/min and should not be used in patients with hepatic impairment^2-6,8.

1.2. Pediatrics

Tramadol IR is FDA-approved for use to manage acute and chronic moderate to moderately severe pain in adolescents 17 years of age and older. Following a titration phase, recommended IR tramadol regimens for pain management include doses of 50 mg to 100 mg administered every 4 to 6 hours as needed. Tramadol ER and tramadol/acetaminophen combination therapy are not FDA-approved for use in pediatric patients as safety and efficacy have not been established and the potential exists for an increased risk of fatal respiratory depression. Pediatric tramadol dosages are summarized in Table 3.

Table 3: Maximum Recommended Pediatric Oral Tramadol Dosages: Monotherapy^2-6
Drug Name	Dosage Forms/Strengths	Maximum Recommended Dose
tramadol immediate-release (Ultram®, generics)	50 mg tablets	Greater than 17 years of age: 400 mg/day, in divided doses every 4-6 hours