Safety Tramadol

The safety of tramadol ER has been established in several double-blind studies of patients with OA or chronic low back pain, or both and one open-label study in patients with chronic noncancer pain conducted within the US (Ultram PI 2006 ). These studies included a total of 3108 patients, of whom 901 were at least 65 years of age (Ultram PI 2006 ). In two 12-week, randomized, double-blind, placebo-controlled studies of patients with chronic non-cancer pain, adverse events increased with dose from 100 mg to 400 mg (Ultram PI 2006 ). The most frequently reported adverse events for tramadol ER 100 to 400 mg ranged from 16% to 28% (dizziness), 15% to 26% (nausea), and 12% to 30% (constipation) (Ultram PI 2006 ). A lower incidence of these adverse events was observed in the placebo group, ranging from 4% to 8% (Ultram PI 2006 ). In the 12-week study of 246 patients with OA recently reported by Babul and colleagues (2004) , the overall incidence of adverse events over the study period was higher for patients receiving tramadol ER compared with placebo (79.0% vs 63.9%; p = 0.011). Adverse events possibly related to treatment were reported for 63.7% and 32% of patients in the tramadol ER and placebo groups, respectively (p < 0.001) (Babul et al 2004 ). More than 90% of the adverse events in both treatment groups were of mild or moderate severity (Babul et al 2004 ). The most frequently reported adverse events in the tramadol ER group were dizziness (33%), constipation (26%), and nausea (24%) (Babul et al 2004 ). In contrast, the incidence of these adverse events was lower in the placebo group, ranging from 6% to 12% (Babul et al 2004 ). Although tramadol ER treatment in this study was initiated at a daily dose of 100 mg, certain patients received dose increases up to 400 mg based on the adequacy of pain relief and tolerability of side effects. Therefore, the 400 mg dose of tramadol ER, which is not approved for treatment of chronic pain, may have contributed to the higher rate of adverse events in this study (Ultram PI 2006 ). Unlike other agents such as nonselective NSAIDs and COX-2 inhibitors, tramadol has no known association with cardiovascular disease or stomach ulcers. Tramadol ER should be used with caution in the geriatric population (Tramadol ER PI 2006). A study of 901 patients at least 65 years of age showed that the incidence of adverse events was highest in the group over 75 years of age receiving tramadol ER (Tramadol PI 2006). Like other opioids, tramadol ER is contraindicated in states of acute intoxication with alcohol, narcotics, hypnotics, centrally acting analgesics, opioids, or psychotropic agents (Ultram PI 2006 ). Tramadol ER use may be limited by its potential to increase risk of seizures (Ultram PI 2006 ). Seizures have been reported in patients taking tramadol within the recommended dose range (Ultram PI 2006 ). Tramadol increased the risk for seizure in patients taking serotonin reuptake inhibitors, tricyclic antidepressants, and opioids (Ultram PI 2006 ). Tramadol ER may also increase the risk for seizure if combined with drugs that decrease seizure threshold, such as monoamine oxidase inhibitors (Ultram PI 2006 ). Furthermore, combination of tramadol ER with central nervous system (CNS) depressants may produce respiratory depression, a reported side effect of opioid therapy (Stephens et al 2003 ; Ultram PI 2006 ). Use of tramadol ER may be limited in patients with renal or hepatic impairment (Ultram PI 2006 ). Following repeated doses of tramadol ER 100 mg, exposure of the tramadol M1 metabolite was increased by 20%-40% in patients with mild (creatinine clearance = 50-80 mL/min) or moderate (creatinine clearance = 30-50 mL/min) renal impairment, compared with normal subjects (Ultram PI 2006 ). Additionally, exposure of the M1 metabolite was decreased by approximately 50% in patients with mild and moderate hepatic impairment, compared with normal subjects (Ultram PI 2006 ). It is recommended that tramadol ER should not be used in patients with severe renal impairment (creatinine clearance <30 mL/min) or severe hepatic impairment (Ultram PI 2006 ).