Tramadol hydrochloride conventional tablets are used orally for the relief of pain that is severe enough to require an opiate analgesic; because of the risks of addiction, abuse, and misuse associated with opiates even at recommended dosages, conventional preparations of tramadol should be reserved for use in patients for whom alternative treatment options (e.g., nonopiate analgesics) have not been, or are not expected to be, adequate or tolerated. Comparative and noncomparative clinical studies have shown that tramadol is an effective analgesic agent in the treatment of moderately severe acute or chronic pain, including postoperative, gynecologic, and obstetric pain, as well as pain of various other origins, including cancer.
Tramadol hydrochloride extended-release capsules and tablets are used for the relief of pain that is severe enough to require long-term, daily, around-the-clock use of an opiate analgesic. Because of the risks of addiction, abuse, and misuse associated with opiates even at recommended dosages, and because of the greater risks of overdose and death associated with extended-release opiate formulations, these extended-release preparations of tramadol should be reserved for use in patients for whom alternative treatment options (e.g., nonopiate analgesics, immediate-release opiates) are inadequate or not tolerated. These extended-release preparations of tramadol are not intended for use on an as-needed (''prn'') basis.
Tramadol hydrochloride in fixed combination with acetaminophen is used for the short-term (5 days or less) management of acute pain that is severe enough to require an opiate analgesic; because of the risks of addiction, abuse, and misuse associated with opiates even at recommended dosages, preparations containing tramadol in fixed combination with acetaminophen should be reserved for use in patients for whom alternative treatment options (e.g., nonopiate analgesics) have not been, or are not expected to be, adequate or tolerated.
Single oral doses of tramadol hydrochloride ranging from 50-200 mg (as conventional tablets) have provided relief of postoperative pain in patients who have undergone various types of surgery, including orthopedic, gynecologic, and cesarean section, and in oral surgical procedures (e.g., extraction of impacted molars). In controlled clinical studies of postoperative pain, tramadol hydrochloride administered as a single oral dose of 150 mg was comparable to, or more effective than, the combination of acetaminophen 650 mg and propoxyphene napsylate 100 mg. In patients undergoing oral surgery, a single oral tramadol hydrochloride dose of 50 or 75 mg provided analgesia in some patients, and a single oral dose of 100 mg provided analgesia that was superior to that provided by 60 mg of codeine sulfate but inferior to the combination of codeine phosphate 60 mg and aspirin 650 mg. In a study of patients undergoing dental extraction, a single oral dose of tramadol hydrochloride 75 or 150 mg was more effective than codeine phosphate 60 mg, and tramadol hydrochloride 150 mg was more effective (while tramadol hydrochloride 75 mg was less effective) than acetaminophen 650 mg and propoxyphene napsylate 100 mg.
In several long-term controlled clinical studies of patients with chronic pain (e.g., low back pain, cancer pain, neuropathic pain, pain associated with orthopedic and joint disorders), tramadol hydrochloride dosages averaging 250 mg daily administered in divided doses as conventional tablets were as effective as acetaminophen 300 mg or aspirin 325 mg administered with codeine phosphate 30 mg 5 times daily or acetaminophen 500 mg administered with oxycodone hydrochloride 5 mg 2 or 3 times daily. Tramadol also may be useful in the management of cancer pain when nonopiate-agonist analgesics are no longer effective (i.e., step 2 of the WHO guidelines for cancer pain treatment). In a study of cancer patients with severe chronic pain, tramadol hydrochloride conventional tablets provided effective analgesia but were less effective than an extended-release morphine dosage form; however, patients receiving tramadol experienced only mild adverse effects, none of which resulted in patient withdrawal from the study, while about 23% of patients receiving extended-release morphine withdrew from the study because of severe adverse effects.
Tolerance to tramadol-induced adverse effects may be increased by initiating therapy with a dosage titration regimen. In clinical studies, the rate of discontinuance of tramadol therapy (as conventional tablets) secondary to adverse effects was decreased by utilizing a 10- or 16-day dosage titration regimen for initiating therapy. Fewer patients discontinued therapy because of dizziness or vertigo when the dosage was titrated over 10 days rather than 4 days; similarly, if the dosage was titrated over 16 days rather than 10 days, fewer patients discontinued therapy because of nausea or vomiting, or any cause. When tramadol hydrochloride conventional tablets are used, the manufacturers currently recommend a dosage titration regimen in patients not requiring rapid onset of analgesic effect.
(See Dosage and Administration.)
The onset and peak of analgesia occur within 1 and 2-4 hours, respectively, after oral administration of tramadol hydrochloride conventional tablets; peak plasma concentrations of racemic tramadol and its O-desmethyl metabolite (M1) are achieved about 2 and 3 hours, respectively, after oral administration, corresponding to the time of peak analgesic effect. The duration of analgesia produced by a single oral dose of tramadol hydrochloride conventional tablets has been reported to be about 3-6 hours. Following oral administration of the drug as extended-release tablets, peak plasma concentrations of tramadol and its M1 metabolite are achieved about 12 and 15 hours, respectively, after a dose. Following oral administration of the drug as extended-release capsules, peak plasma concentrations of tramadol and its M1 metabolite are achieved about 6 and 11 hours, respectively, after a dose.
Efficacy and safety of tramadol hydrochloride extended-release tablets have been evaluated in clinical studies in adults with chronic, moderate to moderately severe pain associated with osteoarthritis and/or low back pain. Adequate evidence of efficacy was demonstrated in 2 of 4 clinical studies. In a placebo-controlled clinical study of 12 weeks' duration in patients with moderate to moderately severe pain associated with osteoarthritis of the knee or hip, therapy with tramadol hydrochloride extended-release tablets (100 and 200 mg daily) was more effective than placebo as evaluated by changes from baseline in the Western Ontario and McMasters Universities (WOMAC) pain subscale. In a placebo-controlled, flexible-dose study of 12 weeks' duration in patients with osteoarthritis of the knee, therapy with tramadol hydrochloride extended-release tablets (average dose: 270 mg daily) was more effective than placebo as measured by change from baseline on the Arthritis Pain Intensity Visual Analog Scale. Efficacy of tramadol hydrochloride extended-release capsules (which are bioequivalent to the extended-release tablets under fasting conditions) has been evaluated in 4 randomized, placebo-controlled clinical studies of 12 weeks' duration. These studies failed to demonstrate efficacy but differed in design from the clinical studies evaluating the extended-release tablets. In 2 clinical studies, tramadol hydrochloride extended-release capsules were evaluated at dosages of 100, 200, and 300 mg daily in patients with moderate to moderately severe osteoarthritis pain of the hip and knee; the other 2 studies were similar in design, but evaluated only a fixed dosage of 300 mg daily (even in patients who responded to a lower dosage).
A variety of drugs have been used for management of pain in patients with osteoarthritis, including oral agents (e.g., acetaminophen, nonsteroidal anti-inflammatory agents [NSAIAs], tramadol), intra-articular agents (e.g., glucocorticoids, sodium hyaluronate), and topical agents (e.g., capsaicin, methylsalicylate). Factors to consider when making treatment decisions for the management of pain in patients with osteoarthritis include the presence of risk factors for serious adverse GI effects or renal toxicity (which may affect decisions regarding use of NSAIAs), existing comorbidities and concomitant therapy, and the adverse effects profiles and costs of specific therapies.
Because there is evidence that acetaminophen can be effective and because of its relative safety and low cost, the American College of Rheumatology (ACR) recommends use of the drug as the initial analgesic for many osteoarthritis patients. Acetaminophen appears to be as effective as NSAIAs for relief of mild to moderate joint pain in many patients with osteoarthritis; however, the drug is not effective in all patients and may not provide adequate relief in those with moderate to severe pain or when joint inflammation is present. An NSAIA can be considered an alternative initial drug of choice for patients with osteoarthritis, especially for those who have moderate to severe pain and signs of joint inflammation, and also can be considered in patients who fail to obtain adequate symptomatic relief with acetaminophen. Tramadol can be considered in patients in whom NSAIAs are contraindicated (e.g., those with renal impairment) or in whom acetaminophen or NSAIAs have not produced an adequate response.
In controlled single-dose studies in patients with acute pain following oral surgery, analgesia provided by tramadol hydrochloride (75 mg) in fixed combination with acetaminophen (650 mg) was comparable to that provided by ibuprofen 400 mg, and superior to that provided by monotherapy with tramadol hydrochloride 75 mg or acetaminophen 650 mg or by placebo. Onset of pain relief occurred in about 17 minutes in patients receiving the fixed combination of tramadol and acetaminophen and about 15 minutes in those receiving acetaminophen alone. Onset of pain relief occurred in about 30 minutes in patients receiving either tramadol alone or ibuprofen. Duration of pain relief was about 5 hours in patients receiving either tramadol in fixed combination with acetaminophen or ibuprofen, but was about 2 hours with administration of tramadol alone and 3 hours with acetaminophen alone.