Tramadol Oral

Pain

Tramadol hydrochloride conventional tablets are used orally for the relief of pain that is severe enough to require an opiate analgesic;^{[1][2][4][8][9][11][16]} 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.^[1] 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.^{[1][2][3][4][6][7][10][11][16][20]}

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.^[53][59] 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.^[53][59] These extended-release preparations of tramadol are not intended for use on an as-needed (''prn'') basis.^[53][59]

Tramadol hydrochloride in fixed combination with acetaminophen (tramadol/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, reserve tramadol/acetaminophen 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.^[51]

Tramadol hydrochloride in fixed combination with celecoxib (celecoxib/tramadol) is used for the management of acute pain in adults that is severe enough to require an opiate analgesic and for which alternative treatments are inadequate; because of the risks of addiction, abuse, and misuse associated with opiates even at recommended dosages, reserve celecoxib/tramadol 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.^[63]

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).^[1][11] In controlled clinical studies of postoperative pain, tramadol hydrochloride administered as a single oral dose of 150 mg was comparable to,^[52] or more effective than,^{[2][3][7][10][11]} the combination of acetaminophen 650 mg and propoxyphene napsylate 100 mg.^{[2][3][7][10][11][52]} 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.^[1] 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.^[11]

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.^[1][52] 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).^{[3][4][6][11][16][20]} 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;^[11][16] 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.^[16]

Tolerance to tramadol-induced adverse effects may be increased by initiating therapy with a dosage titration regimen.^[1] 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.^[1] 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.^[1] When tramadol hydrochloride conventional tablets are used, the manufacturers currently recommend a dosage titration regimen in patients not requiring rapid onset of analgesic effect.^[1] (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;^{[1][4][9][15]} peak plasma concentrations of racemic tramadol and its O-desmethyl metabolite (M1) are achieved about 2 and 3 hours, respectively, after oral administration,^{[1][3][4][11][51]} corresponding to the time of peak analgesic effect.^[1][4] The duration of analgesia produced by a single oral dose of tramadol hydrochloride conventional tablets has been reported to be about 3-6 hours.^[4][15] 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.^[53] 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.^[59]

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.^[53][54][59] Adequate evidence of efficacy was demonstrated in 2 of 4 clinical studies.^[53][59] 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.^[53] 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.^[53][54] 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.^[59] These studies failed to demonstrate efficacy but differed in design from the clinical studies evaluating the extended-release tablets.^[59] 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).^[59]

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).^[55] 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.^[55]

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.^[55] 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.^[55] 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.^[55] 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.^[55]

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.^[21][51] 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.^[21] Onset of pain relief occurred in about 30 minutes in patients receiving either tramadol alone or ibuprofen.^[21][51] 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.^[21][51]

For further information on the role of opiate analgesics in the management of acute or chronic pain,see Uses: Pain, in the Opiate Agonists General Statement 28:08.08.

Administration

Tramadol hydrochloride alone or in fixed combination with acetaminophen or celecoxib is administered orally.^{[1][51][53][59][63]}

Since food does not affect substantially the rate or extent of absorption of tramadol hydrochloride administered alone as conventional tablets, the manufacturers state that conventional tablets of the drug can be taken without regard to food.^[1] Food may decrease the rate and extent of absorption of tramadol when the drug is administered as extended-release tablets (delaying peak plasma concentrations by about 3 hours and decreasing the extent of absorption by about 16%); the manufacturer states that although tramadol hydrochloride extended-release tablets may be administered once daily without regard to food, the extended-release tablets should be administered in a consistent manner relative to food intake.^[53] The manufacturer also recommends that tramadol hydrochloride extended-release capsules be administered in a consistent manner relative to food intake, although the rate and extent of absorption are similar following oral administration with or without food.^[59] Food delays absorption of tramadol hydrochloride and acetaminophen administered in fixed combination, increasing times to peak plasma concentrations by about 35 and 60 minutes, respectively.^[51] However, food does not affect peak plasma concentrations achieved or the extent of absorption of the drugs, and the clinical importance of the delays in absorption is unknown.^[51] The manufacturers make no specific recommendation regarding administration of the fixed-combination preparation with food.^[51]

Tramadol hydrochloride extended-release tablets or capsules should be swallowed whole and should not be broken, crushed, chewed, split, or dissolved, since such physical alteration of the tablets or capsules could result in rapid release of the drug and absorption of a potentially fatal overdose.^[53][59] The extended-release preparations should not be used concomitantly with other tramadol-containing preparations.^[53][59]

For patients receiving tramadol hydrochloride conventional tablets alone for the relief of moderate to moderately severe pain and not requiring rapid onset of analgesic effect, the manufacturers recommend a dosage titration regimen to decrease the likelihood of discontinuance secondary to adverse effects (e.g., nausea, vomiting, dizziness, vertigo) associated with administration at higher initial dosages.^[1]

Dosage

Opiate agonists should be given at the lowest effective dosage and for the shortest duration of therapy consistent with the treatment goals of the patient.^{[1][53][59][411][413][431][432][435]} The initial dosage of tramadol must be individualized, taking into account the patient's severity of pain, response, prior analgesic use, and risk factors for addiction, abuse, and misuse.^[1][53][59] Dosage should be titrated to a level that provides adequate analgesia and minimizes adverse effects.^[1][53][59] If concomitant therapy with other CNS depressants is required, the lowest effective dosages and shortest possible duration of concomitant therapy should be used.^{[1][53][59][700][703]} (See Concomitant Use with Benzodiazepines or Other CNS Depressants under Cautions: Precautions and Contraindications.)

Because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and/or drug therapy in geriatric patients, care should be taken in dosage selection for such patients.^[51] The manufacturers recommend that geriatric patients receive initial dosages of tramadol hydrochloride alone in the lower end of the usual range and that the dosage not exceed 300 mg daily in those older than 75 years of age.^[1] Dosage of tramadol hydrochloride should be titrated slowly in geriatric patients, with close monitoring for CNS and respiratory depression.^[1][53][59]

Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression.^[1][53][59] Patients should be monitored closely for respiratory depression, especially during the first 24-72 hours of therapy and following any increase in dosage.^[1][53][59]

Patients receiving opiate analgesics should be reevaluated continually for adequacy of pain control and for adverse effects, as well as for manifestations of opiate withdrawal and for the development of addiction, abuse, or misuse.^[1][53][59] During long-term therapy, the continued need for opiate analgesics should be continually reevaluated.^[53][59] Frequent communication among the prescriber, other members of the healthcare team, the patient, and the patient's caregiver or family is important during periods of changing analgesic requirements, including the initial dosage titration period.^[1][53][59] Patients with chronic pain who experience episodes of breakthrough pain may require dosage adjustment or supplemental analgesia (i.e., ''rescue'' therapy with an immediate-release analgesic).^[53][59] If the level of pain increases after dosage stabilization, an attempt should be made to identify the source of increased pain before increasing the dosage.^[1][53][59]

For acute pain not related to trauma or surgery, the prescribed quantity should be limited to the amount needed for the expected duration of pain severe enough to require opiate analgesia (generally 3 days or less and rarely more than 7 days).^{[411][433][434][435]}

When opiate analgesics are used for the management of chronic noncancer pain, the US Centers for Disease Control and Prevention (CDC) recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to 50 mg or more of morphine sulfate daily and avoid dosages equivalent to 90 mg or more of morphine sulfate daily or carefully justify their decision to titrate the dosage to such levels.^[411] Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80-120 mg of morphine sulfate daily.^[423][431]

If discontinuance of opiate therapy is required in a patient who may be physically dependent on opiates, the dosage should be tapered gradually to avoid manifestations of abrupt withdrawal.^[1][53][59] When tramadol therapy is discontinued in such patients, dosage generally can be reduced by 25-50% every 2-4 days.^[1][53][59] If manifestations of withdrawal occur, the dosage should be increased to the prior level and tapered more slowly (i.e., by increasing the interval between dosage reductions and/or reducing the amount of each incremental change in dose).^[1][53][59]

For further information on the management of opiate analgesic therapy, see Dosage and Administration: Dosage, in the Opiate Agonists General Statement 28:08.08.

Conventional (Immediate-release) Tablets

Adults with moderate to moderately severe chronic pain not requiring rapid onset of analgesic effect may initially receive tramadol hydrochloride conventional tablets using a dosage titration regimen; the manufacturers recommend an initial dosage of 25 mg daily in the morning, increased by increments of 25 mg every 3 days as separate doses up to a dosage of 25 mg 4 times daily.^[1] Thereafter, daily dosage of conventional tablets may be increased as tolerated by 50 mg every 3 days, up to 50 mg 4 times daily.^[1] Following titration, 50-100 mg of conventional tablets may be administered every 4-6 hours as needed.^[1] Dosages exceeding 400 mg daily are not recommended by the manufacturers.^[1]

Adults requiring rapid onset of analgesia, and in whom the benefit of rapid onset of analgesia outweighs the risk of drug discontinuance secondary to adverse effects associated with higher initial dosage, may receive tramadol hydrochloride conventional tablets in a dosage of 50-100 mg every 4-6 hours.^[1] Dosages exceeding 400 mg daily are not recommended by the manufacturers.^[1]

Tramadol Hydrochloride in Fixed Combination with Acetaminophen

When tramadol hydrochloride is used in fixed combination with acetaminophen for the short-term (5 days or less) management of acute pain in adults, the usual dosage is 75 mg of tramadol hydrochloride every 4-6 hours as needed, up to a maximum of 300 mg daily.^[21][51]

Tramadol Hydrochloride in Fixed Combination with Celecoxib

When tramadol hydrochloride is used in fixed combination with celecoxib for the management of acute pain in adults, the recommended dosage is 2 tablets (containing 56 mg of celecoxib and 44 mg of tramadol hydrochloride each) every 12 hours as needed for relief of pain.^[63]

Extended-release Tablets and Capsules

When tramadol hydrochloride extended-release tablets or capsules are used in the management of chronic pain in adults who are not currently receiving tramadol, the recommended initial dosage is 100 mg once daily.^[53][59] The daily dosage may be increased in 100-mg increments every 5 days as needed and tolerated.^[53][59] Dosages exceeding 300 mg daily are not recommended by the manufacturers.^[53][59]

Because ratios for conversion from other opiate analgesics to extended-release preparations of tramadol hydrochloride have not been established in clinical trials, the manufacturers state that patients being switched from therapy with other opiate agonists should receive an initial tramadol hydrochloride dosage of 100 mg daily as extended-release tablets or capsules.^[53][59] For patients receiving conventional tramadol hydrochloride preparations, the total daily dosage of the drug should be calculated and rounded down to the next lower 100-mg increment for administration as the extended-release tablets or capsules; the dosage may then be adjusted according to patient requirements.^[53][59] Patients being switched from immediate-release to extended-release preparations of tramadol should be monitored closely for sedation and respiratory depression since data establishing the relative bioavailability of these formulations are lacking.^[1] Because of limitations in dose selection, some patients may not be successfully switched from immediate-release to extended-release preparations of the drug.^[53][59] All other around-the-clock opiate analgesics should be discontinued when therapy with the extended-release preparation is initiated.^[53][59]

Dosage in Renal and Hepatic Impairment

Dosage of tramadol hydrochloride (as conventional tablets) should be reduced in certain patients with renal or hepatic impairment by decreasing the frequency of administration.^[1][3][51] Adults with creatinine clearances less than 30 mL/minute may receive oral tramadol hydrochloride conventional tablets in a dosage of 50-100 mg every 12 hours, not to exceed 200 mg daily.^[1] Since less than 7% of a dose of tramadol hydrochloride is removed by hemodialysis, patients undergoing dialysis may receive their usual dosage on the day of dialysis.^[1] Adults with hepatic cirrhosis may receive the conventional tablets in a dosage of 50 mg every 12 hours.^[1]

Tramadol hydrochloride extended-release oral formulations should not be used in patients with severe renal impairment (creatinine clearances less than 30 mL/minute) or severe hepatic impairment (Child-Pugh class C).^[53][59] The available tablet or capsule strengths and once-daily dosing of these formulations do not provide sufficient dosing flexibility for safe use in these patients.^[53][59]

Adults with creatinine clearances of less than 30 mL/minute may receive tramadol hydrochloride in fixed combination with acetaminophen at a dosing interval of every 12 hours; in such patients, the dosage of tramadol hydrochloride administered as the fixed combination should not exceed 75 mg every 12 hours.^[51] Tramadol hydrochloride in fixed combination with acetaminophen should not be used in patients with impaired hepatic function.^[51]

At recommended dosages, tramadol generally is well tolerated.^{[1][10][16][17][20][46]} Adverse effects usually have been mild^{[10][16][17][20]} and similar in incidence to active controls (i.e., acetaminophen 300 mg with codeine phosphate 30 mg and aspirin 325 mg with codeine phosphate 30 mg).^[1][21] The frequency of some adverse effects may be related to dose and route of administration.^[4][46] The most common adverse effects observed with tramadol in controlled clinical trials and open-label extension periods enrolling patients with chronic nonmalignant pain were nervous system effects (e.g., dizziness) and GI disturbances.^{[1][3][53][54]}

Nervous System Effects

The most frequent adverse nervous system effect of tramadol is dizziness^{[1][3][4][7][8][9][10][11][21][38][43][46][51]} or vertigo,^[1][21][46] which occurred in 26, 31, and 33% of patients receiving tramadol hydrochloride conventional tablets for up to 7, 30, and 90 days, respectively, in clinical studies.^[1] In patients receiving tramadol hydrochloride as extended-release tablets in clinical studies, dizziness^[53][54] was reported in about 16, 20, 23, or 28% of patients receiving the drug in a dosage of 100, 200, 300, or 400 mg once daily, respectively.^[53] In patients receiving tramadol hydrochloride as extended-release capsules in clinical studies, dizziness was reported in about 10, 12, or 14% of patients receiving the drug in a dosage of 100, 200, or 300 mg once daily, respectively.^[59] The incidence of dizziness may be dose related.^[46]

Headache^{[1][3][4][7][21][38][43][46]} occurred in 18, 26, and 32% of patients,^[1] and somnolence^{[1][3][4][8][9][11][21][38][43][46][51]} occurred in 16, 23, and 25% of patients receiving the conventional tablets for up to 7, 30, and 90 days, respectively.^[1] Headache was reported in up to 16 or 23% of patients receiving tramadol hydrochloride as extended-release tablets or extended-release capsules, respectively, at recommended dosages (100-300 mg daily) in clinical studies.^[53][59] Somnolence^[53][54][59] or insomnia^[53][59] occurred in up to 11 or 9%, respectively, of patients receiving recommended dosages of tramadol hydrochloride extended-release tablets and in up to 16 or 5%, respectively, of patients receiving recommended dosages of tramadol hydrochloride extended-release capsules in clinical studies.^[53][59] Weakness^[53][54] has been reported in up to 4% of patients receiving the extended-release tablets in recommended dosages.^[53]

CNS stimulation^{[1][4][21][46]} (a composite of nervousness,^[1][21] anxiety,^[1][21] agitation,^[1][21] tremor,^[1][21] spasticity,^[1][21] euphoria,^[1][21] emotional lability,^[1][21] and hallucinations^[1][21] ) occurred in 7, 11, and 14% of patients receiving tramadol hydrochloride conventional tablets for up to 7, 30, and 90 days, respectively.^[1] Asthenia^[1][21][46] occurred in 6, 11, and 12% of patients, and sweating^{[1][3][4][7][9][10][11][20][21][22][46][51]} occurred in 6, 7, and 9% of patients receiving the conventional tablets for up to 7, 30, and 90 days, respectively.^[1] Sweating may be more common following rapid IV injection.^[46] Asthenia^[53] or increased sweating^[53][54] was reported in up to 7 or 4%, respectively, of patients receiving recommended dosages of tramadol hydrochloride extended-release tablets in clinical studies.^[53] Asthenia^[59] or increased sweating^[59] was reported in up to 9% or 7%, respectively, of patients receiving recommended dosages of the extended-release capsules in clinical studies.^[59]

GI Effects

Constipation^{[14][9][21][22][38][43][46][51]} is the most common adverse GI effect of tramadol, occurring in 24, 38, and 46% of patients receiving tramadol hydrochloride conventional tablets for up to 7, 30, and 90 days, respectively, in clinical studies.^[1] Nausea^{[1][3][4][7][8][9][11][20][21][22][38][43][46][51]} occurred in 24, 34, and 40% of patients,^[1] and vomiting^{[1][3][4][7][8][17][20][21][22][43][46]} occurred in 9, 13, and 17% of patients receiving conventional tablets of the drug for up to 7, 30, and 90 days, respectively.^[1] Nausea,^[53][54] constipation,^[53][54] vomiting,^[53][54] or anorexia^[53] has been reported in up to 26, 22, 9, or 5%, respectively, of patients receiving recommended dosages of tramadol hydrochloride extended-release tablets (100-300 mg daily) in clinical studies.^[53] Nausea,^[59] constipation,^[59] vomiting,^[59] or anorexia^[59] has been reported in up to 25, 21, 10, or 6%, respectively, of patients receiving recommended dosages of the extended-release capsules (100-300 mg daily) in clinical studies.^[59] Nausea and vomiting may occur more frequently with higher doses and following rapid IV injection.^[46]

Other adverse GI effects reported in patients receiving conventional tablets of the drug include dyspepsia,^{[1][21][43][51]} which occurred in 5, 9, and 13% of patients, dry mouth,^{[1][3][4][8][11][17][21][43][46][51]} which occurred in 5, 9, and 10%, and diarrhea,^[1][21][46] which occurred in 5, 6, and 10% of patients receiving tramadol for up to 7, 30, and 90 days, respectively.^[1] Dry mouth^[53] or diarrhea^[53] was reported in up to 10 or 9%, respectively, of patients receiving recommended dosages of tramadol hydrochloride extended-release tablets in clinical studies.^[53] Dry mouth^[59] also was reported in up to 13% of patients receiving recommended dosages of the extended-release capsules in clinical studies.^[59]

Sensitivity Reactions

Pruritus^{[1][9][21][22][46][51][53][59]} occurred in 8, 10, and 11% of patients receiving tramadol hydrochloride conventional tablets for up to 7, 30, and 90 days, respectively;^[1] in up to 9% of patients receiving the extended-release tablets in recommended dosages (100-300 mg daily);^[53] and in up to 7% of patients receiving the extended-release capsules in recommended dosages (100-300 mg daily).^[59] Rash^[1][59] or dermatitis^[53] was reported in 1% to less than 5% of patients receiving the drug in clinical trials.^[1][53][59] Serious and rarely fatal anaphylactoid reactions, often occurring after the initial dose, have been reported in patients receiving tramadol.^[1][46][53] (See Cautions: Precautions and Contraindications.) Urticaria,^[1][53][59] bronchospasm,^[1][53][59] and angioedema^[1][53][59] have occurred.^[1][53][59]

Cardiovascular Effects

Vasodilation^[1] has been reported in 1% to less than 5% of patients receiving tramadol hydrochloride conventional tablets in clinical trials.^[1] Postural hypotension^[53] or flushing^[53] occurred in up to 4 or 10%, respectively, of patients receiving tramadol hydrochloride extended-release tablets in recommended dosages (100-300 mg daily) in clinical studies.^{[53] [53]}

Genitourinary and Endocrine Effects

Hypoglycemia has been reported very rarely in patients receiving tramadol, mainly in patients with predisposing risk factors (e.g., diabetes mellitus, renal insufficiency) or in geriatric patients.^[1][53] Increased blood glucose concentrations have occurred in patients receiving tramadol hydrochloride extended-release tablets.^[53]

Adrenal insufficiency has been reported in patients receiving opiate agonists or opiate partial agonists.^{[1][53][59][400]} Manifestations of adrenal insufficiency are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.^{[1][53][59][400]} The onset generally has occurred after at least 1 month of opiate agonist or partial agonist use, although the time to onset has ranged from within 1 day to more than 1 year.^{[1][53][59][400]} In many of the reported cases, patients required hospitalization.^[400] If adrenal insufficiency is suspected, appropriate laboratory testing should be performed promptly and physiologic (replacement) dosages of corticosteroids provided; therapy with the opiate agonist or partial agonist should be tapered and discontinued to allow recovery of adrenal function.^{[1][53][59][400]} If the opiate agonist or partial agonist can be discontinued, follow-up assessment of adrenal function should be performed to determine if corticosteroid replacement therapy can be discontinued.^[400] In some patients, switching to a different opiate improved symptoms.^{[1][53][59][400]}

Hypogonadism and androgen deficiency have been reported in patients receiving long-term opiate agonist or opiate partial agonist therapy,^{[400][401][402][403][404]} although a causal relationship has not been established.^{[1][53][59][400]} Patients receiving long-term opiate agonist or partial agonist therapy who present with manifestations of hypogonadism (e.g., decreased libido, impotence, erectile dysfunction, amenorrhea, infertility) should undergo laboratory evaluation.^[400]

Acute Toxicity

Manifestations

Tramadol taken in excessive doses, either alone or in combination with other CNS depressants, is a cause of drug-related deaths.^[1][53] Fatalities associated with both intentional and unintentional overdose have been reported.^{[1][21][40][52][53]} Estimates of ingested dose in non-US fatalities ranged from 3-5 g.^[21][52] A 3-g intentional overdose by a patient enrolled in a clinical trial produced emesis and no sequelae.^[21][52] The lowest tramadol hydrochloride dose reportedly associated with fatality was possibly between 0.5-1 g in a 40-kg woman, but details of the case are not completely known.^[21][52] Tramadol is intended for oral use only.^[1][53][59] Crushing, cutting, breaking, or chewing tramadol hydrochloride extended-release tablets or capsules, ''snorting'' the powder, or injecting dissolved contents of the tablets or capsules results in uncontrolled delivery of tramadol and poses a risk of a potentially fatal overdose.^[53][59] The risk of a fatal overdose is increased when tramadol is misused concurrently with other CNS depressants (e.g., alcohol, other opiates).^[1][53][59] Manifestations of overdosage are similar to those of other opiate agonists, with the most serious potential consequences being respiratory depression, lethargy, skeletal muscle flaccidity, coma, seizure, bradycardia, hypotension, pulmonary edema, partial or complete airway obstruction, cardiac arrest, cardiac collapse, and death.^{[1][3][21][52][53][59]} Death may occur within 1 hour of overdosage.^[53] Other manifestations may include miosis,^[21] vomiting,^[21] cold and clammy skin,^[1][51][53] and atypical snoring.^[1][53][59] Marked mydriasis (rather than miosis) may be observed in patients with hypoxia.^[1][53][59]

Treatment

When treating tramadol overdosage, primary attention should be given to maintaining adequate ventilation along with general supportive treatment (including administration of oxygen and vasopressors as clinically indicated).^[1][53][59] Tramadol hydrochloride extended-release tablets or capsules will continue to release the drug for 24-48 hours or longer following ingestion, necessitating prolonged monitoring.^[53][59] An opiate antagonist should be administered if clinically important respiratory or circulatory depression is present, but should not be administered in the absence of such manifestations.^[1][53][59] Although an opiate antagonist (e.g., naloxone, nalmefene) will reverse some, but not all, manifestations of tramadol overdosage, the risk of seizures also is increased with naloxone administration.^{[1][3][4][21][53][59]} In animals, seizures following the administration of toxic tramadol doses could be suppressed with barbiturates or benzodiazepines but were increased with naloxone.^[1][53][59] Naloxone administration did not change the lethality of an overdose in mice.^[1][53][59] Hemodialysis is unlikely to be helpful in a tramadol overdosage because it removes less than 7% of the administered dose in a 4-hour dialysis period.^[1][53][59] .

Precautions and Contraindications

General Opiate Agonist Precautions

Administration of tramadol may cause effects similar to those produced by other opiate agonist drugs,^{[1][2][3][4][5][7][8][9][11][53]} and the usual precautions of opiate agonist therapy should be observed.^[1][53][59] (See Description and the manufacturers' labeling.)

Extended-release preparations of tramadol should be prescribed only by clinicians who are knowledgeable in the use of potent opiates for the management of chronic pain.^[53][59]

Addiction, Abuse, and Misuse

Tramadol exposes patients and other users to the risks of opiate addiction (opiate use disorder [OUD]), abuse, and misuse, which can lead to overdosage and death.^[1][53][59] The abuse potential of tramadol is less than that of morphine or oxycodone but similar to that of propoxyphene (see Description).^[56] Addiction can occur with appropriately prescribed or illicitly obtained opiates, and at recommended dosages or with misuse or abuse.^[1][53][59] Concurrent abuse of alcohol or other CNS depressants increases the risk of toxicity.^[1][53][59] Each patient's risk for addiction, abuse, and misuse should be assessed prior to initiating tramadol therapy, and all patients receiving the drug should be monitored for development of these behaviors or conditions.^[1][53][59] Personal or family history of substance abuse (drug or alcohol addiction or abuse) or mental illness (e.g., major depression) increases risk.^[1][53][59] The potential for addiction, abuse, and misuse should not prevent opiate prescribing for appropriate pain management, but does necessitate intensive counseling about risks and proper use and intensive monitoring for signs of addiction, abuse, and misuse.^[1][53][59] Tramadol should be prescribed in the smallest appropriate quantity and the patient should be instructed on secure storage and proper disposal to prevent theft.^[1][53][59]

Extended-release opiates are associated with a greater risk of overdosage and death because of the larger amount of drug contained in each dosage unit.^[53][59] Abuse or misuse of tramadol extended-release tablets or capsules by splitting, crushing, breaking, cutting, or chewing the tablets or capsules, snorting the contents, or injecting the dissolved contents will result in uncontrolled delivery of tramadol and can result in a fatal overdosage.^[53][59] IV injection of excipients in these formulations can result in local tissue necrosis, infection, pulmonary granulomas, embolism, and death and increase the risk of endocarditis and valvular heart injury.^[53][59]

Respiratory Depression

Serious, life-threatening, or fatal respiratory depression can occur in patients receiving opiates, even when used as recommended.^[1][53][59] Although respiratory depression can occur at any time during therapy, the risk is greatest during initiation of therapy and following an increase in dosage; therefore, patients receiving tramadol should be monitored closely for respiratory depression, especially during the first 24-72 hours of therapy and following any increase in dosage.^[1][53][59] Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression.^[1][53][59] Large initial doses in nontolerant patients, overestimation of the initial tramadol dosage when transferring patients from another opiate analgesic, or accidental ingestion of even one dose of tramadol, especially by a child, can result in respiratory depression and death.^[1][53][59] For clinically important respiratory depression resulting from tramadol overdosage, an opiate antagonist should be administered.^[1][53][59] (See Treatment under Cautions: Acute Toxicity.)

Geriatric, cachectic, or debilitated patients are at increased risk of life-threatening respiratory depression.^[1][53][59] In patients with chronic obstructive pulmonary disease or cor pulmonale, substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, even recommended doses of tramadol may decrease respiratory drive to the point of apnea.^[1][53][59] Such patients should be monitored closely, particularly following initiation of therapy, during dosage titration, and during concomitant therapy with other respiratory depressants.^[1][53][59] Alternatively, use of nonopiate analgesics should be considered in such patients.^[1][53][59] Use of tramadol in patients with substantial respiratory depression or in those with severe bronchial asthma in unmonitored settings or in the absence of resuscitative equipment is contraindicated.^[1][53][59]

Because of the risks associated with opiate overdosage, clinicians should routinely discuss the availability of the opiate antagonist naloxone with all patients receiving new or reauthorized prescriptions for opiate analgesics, including tramadol.^[750] Clinicians should consider prescribing naloxone for patients receiving opiate analgesics who are at increased risk of opiate overdosage (e.g., those receiving concomitant therapy with benzodiazepines or other CNS depressants, those with a history of opiate or substance use disorder, those with medical conditions that could increase sensitivity to opiate effects, those who have experienced a prior opiate overdose)^{[411][431][750]} or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.^[750] Even if patients are not receiving an opiate analgesic, a naloxone prescription should be considered if the patient is at increased risk of opiate overdosage (e.g., those with a current or past diagnosis of OUD, those who have experienced a prior opiate overdose).^[750] (See Naloxone Hydrochloride 28:10.)

Drugs Affecting Hepatic Microsomal Enzymes

Because orally administered tramadol undergoes extensive hepatic metabolism, including metabolism by cytochrome P-450 (CYP) isoenzymes 2D6 and 3A4, concomitant use of drugs that inhibit or induce CYP3A4 or inhibit CYP2D6 requires careful consideration of the effects on tramadol and its active O-desmethyl metabolite (M1) (see Description).^[1][53][59]

Because formation of M1 is dependent on CYP2D6 activity, concomitant use of tramadol and CYP2D6 inhibitors (e.g., amiodarone, bupropion, fluoxetine, paroxetine, quinidine) may result in increased plasma concentrations of tramadol and decreased concentrations of M1, particularly when the CYP2D6 inhibitor is initiated after a stable dosage of tramadol has been achieved.^[1][53][59] The increase in tramadol concentrations can result in increased or prolonged therapeutic effects and an increased risk of serious adverse effects, including seizures and serotonin syndrome, while the decrease in M1 concentrations may result in reduced therapeutic effects and, in patients physically dependent on opiates, manifestations of opiate withdrawal.^[1][53][59] Discontinuance of the CYP2D6 inhibitor may result in a decrease in plasma concentrations of tramadol and an increase in M1 concentrations, which could increase or prolong therapeutic effects or manifestations of opiate toxicity and potentially cause fatal respiratory depression.^[1][53][59] If concomitant therapy with tramadol and a CYP2D6 inhibitor is required, patients should be monitored closely for serious tramadol-related adverse effects (including seizures and serotonin syndrome) and manifestations of opiate toxicity or opiate withdrawal.^[1][53][59] If concomitant therapy with a CYP2D6 inhibitor is discontinued, the patient should be monitored closely for adverse effects, including respiratory depression and sedation, and consideration should be given to reducing the tramadol dosage until stable drug effects are achieved.^[1][53][59]

Concomitant use of tramadol and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole antifungals (e.g., ketoconazole), or HIV protease inhibitors (e.g., ritonavir), can increase plasma concentrations of tramadol, which may result in larger amounts of parent drug being metabolized by CYP2D6 and higher concentrations of M1.^[1][53][59] If concomitant therapy with tramadol and a CYP3A4 inhibitor is required, patients should be monitored closely for serious adverse effects (including seizures and serotonin syndrome) and for manifestations of opiate toxicity (including sedation and potentially fatal respiratory depression), particularly when the CYP3A4 inhibitor is initiated after a stable dosage of tramadol has been achieved, and consideration should be given to reducing the tramadol dosage until stable drug effects are achieved.^[1][53][59] If concomitant therapy with a CYP3A4 inhibitor is discontinued, the patient should be monitored for manifestations of opiate withdrawal, and consideration should be given to increasing the tramadol dosage until stable drug effects are achieved.^[1][53][59]

Concomitant use of tramadol and CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin) can decrease plasma concentrations of tramadol, resulting in decreased efficacy and, in patients who are physically dependent on opiates, manifestations of opiate withdrawal.^[1][53][59] Discontinuance of the CYP3A4 inducer may result in increased plasma concentrations of tramadol, which could increase or prolong both the therapeutic and adverse effects of tramadol and may cause seizures, serotonin syndrome, and potentially fatal respiratory depression.^[1][53][59] If concomitant therapy with tramadol and a CYP3A4 inducer is required, patients should be monitored for manifestations of opiate withdrawal, and consideration should be given to increasing the tramadol dosage until stable drug effects are achieved.^[1][53][59] If concomitant therapy with a CYP3A4 inducer is discontinued, patients should be monitored for seizures, serotonin syndrome, sedation, and respiratory depression, and consideration should be given to decreasing the tramadol dosage until stable drug effects are achieved.^[1][53][59]

Concomitant use of tramadol with carbamazepine is not recommended because carbamazepine increases tramadol metabolism and substantially reduces tramadol's analgesic effect, and because tramadol is associated with increased risk of seizures.^[1][53][59]

Concomitant Use with Benzodiazepines or Other CNS Depressants

Tramadol may potentiate the respiratory and CNS depressant effects of other CNS depressants.^{[1][11][21][38][53][59]} Concomitant use of tramadol with benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiate agonists, alcohol) may result in profound sedation, respiratory depression, hypotension, coma, and death.^{[1][53][59][416][417][418][700][701][702][703]} (See Cautions: Acute Toxicity.) Concomitant use of such drugs should be reserved for patients in whom alternative treatment options are inadequate; the lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.^{[1][53][59][700][703]} Concomitant use with alcohol should be avoided.^{[1][53][59][700][703]} Clinicians should consider prescribing the opiate antagonist naloxone for patients receiving opiates who are at increased risk of opiate overdosage, including those receiving benzodiazepines or other CNS depressants concomitantly.^{[411][431][750]} (See Drug Interactions: Benzodiazepines and Other CNS Depressants, in the Opiate Agonists General Statement 28:08.08.)

If a benzodiazepine or other CNS depressant is required for any indication other than epilepsy in a patient receiving tramadol, the drug should be initiated at a lower dosage than indicated in the absence of opiate therapy and titrated based on clinical response.^[700][703] In patients receiving a CNS depressant, tramadol, if required, should be initiated at a reduced dosage and titrated based on clinical response.^{[1][53][59][700][703]}

Serotonin Syndrome

Potentially life-threatening serotonin syndrome may occur with tramadol, particularly with concurrent use of other serotonergic drugs,^{[1][53][59][400]} drugs that impair the metabolism of serotonin (e.g., monoamine oxidase [MAO] inhibitors),^{[1][53][59][400]} or drugs that impair the metabolism of tramadol (e.g., inhibitors of CYP2D6 and CYP3A4).^[1][53][59] Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).^{[1][53][59][400]} Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.^{[1][53][59][400]} (See Drugs Associated with Serotonin Syndrome under Cautions: Precautions and Contraindications.)

Seizures

Seizures have occurred during tramadol therapy with recommended dosages.^{[1][21][38][39][43][44][45][46][53][59]} Spontaneous postmarketing reports indicate that seizure risk is increased with tramadol doses above the recommended range.^{[1][38][39][43][44][46][53][59]} Seizures can occur following the first dose.^[46][53] The manufacturers warn that tramadol increases the seizure risk in patients taking selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), anorectic agents, tricyclic antidepressants or other tricyclic compounds (e.g., cyclobenzaprine, promethazine), or other opiate agonists.^{[1][43][44][46][53][59]} The manufacturers also warn that the drug may enhance the risk of seizure in those receiving MAO inhibitors, antipsychotic agents, or other drugs that decrease the seizure threshold.^{[1][21][43][46][53][59]} Patients with epilepsy, those with a history of seizures, or patients with a recognized risk for seizure (e.g., head trauma, metabolic disorders, alcohol and drug withdrawal, CNS infections) may be at increased risk of seizure.^{[1][21][43][46][53][59]} Naloxone administration in patients with tramadol overdose also may increase the risk of seizure.^{[1][43][46][53][59]}

Suicide

Tramadol should not be prescribed for individuals who are suicidal or prone to addiction.^[1][53][59] Tramadol should be used with caution in patients with a history of misuse, patients receiving concomitant therapy with CNS-active drugs including tranquilizers or antidepressants, individuals with excessive alcohol consumption, and patients with emotional disturbances or depression.^[1][53][59] The use of alternative analgesics without opiate agonist activity should be considered in suicidal or depressed patients.^[1][53][59] (See Cautions: Acute Toxicity.)

Monoamine Oxidase Inhibitors

Concomitant use of opiates with MAO inhibitors (e.g., linezolid, phenelzine, tranylcypromine) may increase the risk of serotonin syndrome, seizures, and opiate toxicity (e.g., respiratory depression, coma).^[1][53][59] Use of tramadol is contraindicated in patients who are currently receiving or have recently (within 14 days) received an MAO inhibitor.^[1][53][59]

Pharmacogenomics

Tramadol is metabolized by the CYP microsomal enzyme system, principally by CYP2D6 to its active M1 metabolite.^[59][60] Metabolism of certain drugs, including tramadol, is influenced by CYP2D6 polymorphism.^{[59][60][108][109][110][112][114]} Individuals who lack functional alleles of the CYP2D6 gene are described as poor metabolizers, those with one or two functional alleles are described as extensive metabolizers, and those who carry a duplicate or amplified gene are described as ultrarapid metabolizers.^{[108][109][110][114]} Population pharmacokinetic analysis of phase 1 studies of tramadol hydrochloride conventional tablets in healthy individuals indicated that concentrations of tramadol were approximately 20% higher and those of M1 were 40% lower in poor metabolizers compared with extensive metabolizers.^[1][53][59]

Genetically determined differences in drug metabolism can affect an individual's response to a drug or risk of having an adverse event.^{[108][109][110][112][114]} Individuals who are poor metabolizers may experience reduced analgesic effects of tramadol;^[60] individuals who are ultrarapid metabolizers are likely to have higher than expected serum concentrations of M1.^[60][705] To minimize the risk of adverse events in individuals who are ultrarapid metabolizers of CYP2D6, FDA states that tramadol should not be used in such patients.^[705] Variations in CYP2D6 polymorphism occur at different frequencies among subpopulations of different ethnic or racial origin.^{[107][108][109][110][114]} Approximately 1-7% of Caucasians and 10-30% of Ethiopians and Saudi Arabians carry the genotype associated with ultra-rapid metabolism of CYP2D6 substrates.^{[107][108][110][114]}

Drugs Associated with Serotonin Syndrome

Serotonin syndrome may occur when tramadol is used concurrently with other serotonergic drugs, including serotonin (5-hydroxytryptamine; 5-HT) type 1 (5-HT₁) receptor agonists (''triptans''), SSRIs, SNRIs, tricyclic antidepressants, antiemetics that are 5-HT₃ receptor antagonists, buspirone, cyclobenzaprine, dextromethorphan, lithium, St. John's wort (Hypericum perforatum), tryptophan, other serotonin modulators (e.g., mirtazapine, nefazodone, trazodone, vilazodone), and MAO inhibitors (both those used to treat psychiatric disorders and others, such as linezolid, methylene blue, and selegiline).^{[1][47][53][59][400]} Serotonin syndrome may occur within the recommended dosage ranges for these drugs.^{[1][53][59][400]} Serotonin syndrome has been reported during postmarketing experience in patients receiving tramadol concomitantly with MAO inhibitors, SSRIs, SNRIs, or α₂-adrenergic blocking agents.^{[1][47][53][59]} Tramadol decreases the synaptic reuptake of the monoamine neurotransmitters norepinephrine and serotonin,^{[1][4][11][12][13][14]} and animal studies have shown increased deaths with combined administration of tramadol and MAO inhibitors.^[1][53][59] Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).^{[1][53][59][400]} Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.^{[1][53][59][400]}

If concomitant use of other serotonergic drugs is warranted, great caution is advised^{[1][3][8][9][11][38][43][53][59]} and patients should be monitored for serotonin syndrome, particularly during initiation of therapy and dosage increases.^{[1][47][53][59][400]} If serotonin syndrome is suspected, treatment with tramadol, other opiate therapy, and/or any concurrently administered serotonergic agents should be discontinued.^[400]

For further information on serotonin syndrome, including manifestations and treatment, see Drug Interactions: Serotonergic Drugs, in Fluoxetine Hydrochloride 28:16.04.20.

Hypotension

Tramadol may cause severe hypotension, including orthostatic hypotension and syncope, in ambulatory patients.^[1][53][59] Because the risk of severe hypotension is increased in patients whose ability to maintain blood pressure has been compromised by blood volume depletion or concomitant use of certain CNS depressants (e.g., phenothiazines, general anesthetics), such patients should be monitored for hypotension following initiation of tramadol therapy or an increase in tramadol dosage.^[1][53][59] Use of tramadol should be avoided in patients with circulatory shock since the drug may cause vasodilation that can further reduce cardiac output and blood pressure.^[1][53][59]

Increased Intracranial Pressure or Head Injury

The respiratory depressant effects of opiate agonists promote carbon dioxide retention, which can result in elevation of intracranial pressure.^[1][53][59] Patients who may be particularly susceptible to these effects (e.g., those with evidence of elevated intracranial pressure or brain tumors) should be monitored closely for sedation and respiratory depression, particularly during initiation of therapy.^[1][53][59] Opiates also may obscure the clinical course in patients with head injuries.^[1][53][59] Use of tramadol should be avoided in patients with impaired consciousness or coma.^[1][53][59]

GI Conditions

Opiates may increase serum amylase concentrations and cause spasm of the sphincter of Oddi.^[1][53][59] Patients with biliary tract disease, including those with acute pancreatitis, should be monitored for worsening symptoms.^[1][53][59] Tramadol is contraindicated in patients with known or suspected GI obstruction, including paralytic ileus.^[1][53][59]

Sensitivity Reactions

Serious and rarely fatal anaphylactoid reactions have been reported in patients receiving tramadol.^{[1][46][53][59]} These reactions often occur following the first dose.^{[1][46][53][59]} Other reported hypersensitivity reactions include pruritus, urticaria, angioedema, bronchospasm, toxic epidermal necrolysis, and Stevens-Johnson syndrome.^[1][53][59] The manufacturers warn that patients with a history of anaphylactoid reactions to codeine or other opiate agonists may be at increased risk and therefore should not receive tramadol.^{[1][46][53][59]} If anaphylaxis or other hypersensitivity reaction occurs, tramadol should be discontinued immediately and permanently.^[1][53][59]

Dependence and Tolerance

Both tolerance and physical dependence can develop during long-term opiate therapy.^[1][53][59] Tolerance may not develop uniformly to all opiate effects.^[1][53][59]

In patients who are physically dependent on opiates, abrupt discontinuance of tramadol or a substantial reduction in dosage may result in manifestations of withdrawal (e.g., restlessness, lacrimation, rhinorrhea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increases in blood pressure, respiratory rate, or heart rate).^[1][53][59] When tramadol therapy is discontinued in a patient who may be physically dependent on opiates, the dosage should be tapered gradually.^[1][53][59] Infants born to women who are physically dependent on opiates also will be physically dependent.^[1][53][59] (See Cautions: Pregnancy, Fertility, and Lactation.)

Concomitant use of opiate partial agonists (e.g., buprenorphine, butorphanol, nalbuphine, pentazocine) should be avoided since they may reduce the analgesic effect of tramadol and/or precipitate withdrawal symptoms.^[1][53][59]

CNS Depression

Tramadol may impair mental alertness and/or physical coordination required to perform potentially hazardous activities such as driving or operating machinery; patients should be warned about possible adverse CNS effects of the drug.^[1][53][59]

Warfarin

Prolongation of the international normalized ratio (INR)^[48][49][50] and prothrombin time^{[1][49][53][59]} and extensive ecchymoses^[49] have been reported in patients receiving tramadol and warfarin concomitantly.^{[1][48][49][50][53][59]} Therefore, tramadol should be used with caution in patients receiving warfarin;^[49] the INR should be closely monitored in those receiving the combination,^[48][49][50] and the warfarin dosage should be adjusted as needed.^[1][53][59]

Digoxin

Digoxin toxicity has been reported rarely during postmarketing experience in patients receiving digoxin and tramadol concomitantly.^[1][53][59] Patients receiving such concomitant therapy should be monitored for digoxin toxicity, and digoxin dosage should be adjusted as needed.^[1][53][59]

Renal and Hepatic Impairment

Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active O-desmethyl metabolite (M1).^{[1][43][53][59]} Therefore, in patients with creatinine clearance less than 30 mL/minute, the manufacturers recommend dosage reduction when tramadol is used alone as conventional tablets or in fixed combination with acetaminophen.^{[1][9][43][51]} Tramadol hydrochloride extended-release tablets and capsules should not be used in patients with severe renal impairment (i.e., creatinine clearance less than 30 mL/minute); the available tablet and capsule strengths and once-daily dosing do not provide sufficient dosing flexibility for safe use in these patients.^[53][59] (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Tramadol and M1 metabolism are reduced in patients with advanced hepatic cirrhosis.^{[1][9][43][53]} When tramadol hydrochloride conventional tablets are used in adults with cirrhosis, dosage adjustment is recommended.^[1] Tramadol hydrochloride extended-release tablets and capsules should not be used in patients with severe hepatic impairment (Child-Pugh class C); the available tablet and capsule strengths and once-daily dosing do not provide sufficient dosing flexibility for safe use in these patients.^[53][59] The manufacturers state that pharmacokinetics and safety of tramadol in fixed combination with acetaminophen have not been studied in patients with impaired hepatic function.^[51] Therefore, because both tramadol and acetaminophen are extensively metabolized by the liver, the fixed-combination preparation should not be used in patients with hepatic impairment.^[51] (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

With the prolonged half-life of tramadol in patients with renal or hepatic impairment, achievement of steady-state plasma concentrations is delayed, and it may take several days for elevated plasma concentrations to occur.^[1]

Advice to Patients

Patients should be advised to read the manufacturer's patient information (e.g., medication guide) for tramadol before initiating therapy with the drug and each time the prescription is refilled.^[1][53][59] Patients should be informed that use of tramadol, even when taken as recommended, can result in addiction, abuse, and misuse, which can lead to overdosage and death.^[1][53][59] Patients also should be informed that accidental ingestion of tramadol, especially by a child, may result in respiratory depression or death.^[1][53][59] Patients should be instructed not to share the drug with others, to take steps to protect the drug from theft or misuse, to securely store the drug, to keep the drug out of reach of children, and to properly dispose of any unused drug.^[1][53][59]

Patients should be advised of the risk of life-threatening respiratory depression and instructed to seek immediate medical attention if manifestations of respiratory depression occur.^[1][53][59] Patients receiving tramadol and/or their caregivers should be advised that concomitant therapeutic or illicit use of benzodiazepines or other CNS depressants, including alcohol, can result in potentially fatal additive effects (e.g., profound sedation, respiratory depression, coma); patients should be advised to avoid concomitant use of alcohol and to avoid concomitant use of other CNS depressants unless such use is supervised by a clinician.^{[1][53][59][700]} Patients should be advised of the benefits of naloxone administration following an overdose and of their options for obtaining the drug.^[750]

Patients should be informed of the risk of opiate toxicity in children, especially those who are obese, have respiratory diseases, or have evidence of ultrarapid metabolism of tramadol^[60][705] and advised that tramadol should not be given to children younger than 12 years of age for pain relief or to children younger than 18 years of age for pain relief following tonsillectomy or adenoidectomy.^[705] (See Cautions: Pediatric Precautions.)

Patients should be advised that tramadol may cause seizures and/or serotonin syndrome, particularly when used concurrently with serotonergic drugs or drugs that substantially decrease the metabolism of tramadol.^{[1][53][59][400]} (See Drugs Associated with Serotonin Syndrome and also Drugs Affecting Hepatic Microsomal Enzymes under Cautions: Precautions and Contraindications.) Patients should be advised that tramadol may impair mental or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery.^[1][53][59] Patients should be advised of the importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses; patients should be advised that tramadol should not be used concomitantly with MAO inhibitors.^[1][53][59] Patients also should be advised that severe hypersensitivity reactions have occurred and that the drug may cause orthostatic hypotension and syncope.^[1][53][59] Because opiates can cause severe constipation, patients should be advised on appropriate management of constipation.^[1][53][59] Because of the potential risk of adrenal insufficiency, patients should be advised to immediately contact a clinician if manifestations of adrenal insufficiency (e.g., nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, hypotension) develop.^{[1][53][59][400]} Although a causal relationship between hypogonadism or androgen deficiency and long-term opiate agonist use has not been established, patients should be advised of this potential risk and instructed to inform their clinician if decreased libido, impotence, erectile dysfunction, amenorrhea, or infertility occurs.^[400]

Women of childbearing potential should be instructed to inform their clinician if they are or plan to become pregnant^[1][53][59] and should be advised that use of tramadol is not recommended in nursing women.^{[1][53][59][705]} Women of childbearing potential should be advised that tramadol may cause fetal harm and that prolonged use of opiates during pregnancy may result in neonatal opiate withdrawal syndrome, which can be life-threatening if not recognized and treated.^[1][53][59] (See Cautions: Pregnancy, Fertility, and Lactation.)

Clinicians should be certain that patients understand the single-dose and 24-hour dose limit, and the recommended interval between doses of tramadol administered alone or in fixed combination with acetaminophen, since exceeding these recommendations can result in respiratory depression, seizures, acetaminophen-associated hepatic toxicity, and death.^{[1][51][53][59]} Patients receiving therapy with tramadol hydrochloride extended-release tablets or capsules should be advised that the tablets or capsules should be swallowed whole and should not be crushed, chewed, broken, split, or dissolved.^[53][59] Because of the risk of withdrawal syndrome, patients should be advised not to abruptly discontinue therapy with the drug without consulting their clinician.^[1][53][59]

Contraindications

Tramadol is contraindicated in patients with substantial respiratory depression; acute or severe bronchial asthma in unmonitored settings or in the absence of resuscitative equipment; known or suspected GI obstruction, including paralytic ileus; or known hypersensitivity (e.g., anaphylaxis) to the drug, other opiates, or any ingredient in the formulation.^[1][53][59] Tramadol also is contraindicated during or within 14 days following treatment with an MAO inhibitor.^[1][53][59]

Tramadol is contraindicated in children younger than 12 years of age for the management of pain and in those younger than 18 years of age for the management of postoperative pain following tonsillectomy and/or adenoidectomy.^[705] (See Cautions: Pediatric Precautions.)

Pediatric Precautions

Children receiving tramadol for the management of pain, especially those who are obese, have obstructive sleep apnea or severe lung disease, or have evidence of ultrarapid metabolism of CYP2D6 substrates, are at increased risk of respiratory depression.^[705] Between January 1969 and May 2016, the FDA Adverse Event Reporting System (AERS) received 9 reports of respiratory depression, including 3 deaths, worldwide that were associated with tramadol use in children younger than 18 years of age.^[705] Respiratory depression generally occurred within the first 24 hours of dosing and required medical intervention (e.g., naloxone).^[705] All 3 of the fatal cases occurred outside of the US in children younger than 6 years of age receiving tramadol hydrochloride oral solution for postoperative analgesia or management of fever.^[705] One 5-year-old child with obstructive sleep apnea experienced severely slowed and difficult breathing requiring emergency intervention and hospitalization after receiving a single 20-mg dose of tramadol hydrochloride oral solution (approximately 1 mg/kg) for pain relief following tonsillectomy and adenoidectomy.^{[57][58][705]} The child was resuscitated and later found to be a CYP2D6 ultra-rapid metabolizer and to have a high concentration of the active O-desmethyl metabolite (M1).^{[57][58][705]} In the other 8 reported cases, the CYP2D6 metabolizer status was unknown.^[705]

To minimize the risk of serious adverse events in children, FDA states that tramadol-containing preparations must not be used for the management of pain in children younger than 12 years of age or for the management of postoperative pain following tonsillectomy and/or adenoidectomy in children younger than 18 years of age.^[705] FDA also states that use of tramadol for the management of pain is not recommended in children 12-18 years of age who are obese or have conditions such as obstructive sleep apnea or compromised respiratory function (because of potentially greater susceptibility to the respiratory depressant effects of the drug).^[705] If tramadol is used for the management of pain in children 12-18 years of age, caregivers should closely monitor the child for clinical manifestations of opiate toxicity (e.g., slow, shallow, difficult, or noisy breathing; confusion; unusual sleepiness) and seek immediate medical treatment for the child if such manifestations occur.^[705]

The manufacturers state that safety and efficacy of tramadol hydrochloride conventional tablets have not been established in children younger than 16 years of age.^[1] Safety and efficacy of tramadol hydrochloride extended-release tablets and capsules and of tablets containing tramadol hydrochloride in fixed combination with acetaminophen have not been established in children younger than 18 years of age.^[51][53][59] The manufacturers state that use of tramadol in pediatric patients is not recommended.^{[1][51][53][59]}

Geriatric Precautions

In general, tramadol dosage should be titrated carefully in geriatric patients, usually initiating therapy at the low end of the dosage range, considering the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly. ^[51] (See Dosage and Administration: Dosage.) Because respiratory depression is the chief risk for geriatric patients receiving opiates, dosage should be titrated slowly and geriatric patients should be monitored closely for CNS and respiratory depression.^[1][53][59] Tramadol is substantially excreted by the kidneys, and the risk of adverse effects may be increased in patients with impaired renal function.^[1][53][59] Because geriatric patients may have decreased renal function, dosage should be selected carefully; it may be useful to monitor renal function in such patients.^[1][53][59]

In controlled clinical trials of tramadol hydrochloride conventional tablets, 455 patients who received the drug were 65 years of age or older, while 145 patients were 75 years of age or older.^[1] In patients older than 75 years of age receiving conventional tablets of the drug, maximum serum tramadol concentrations are elevated (208 ng/mL) and the elimination half-life is prolonged (7 hours) compared with patients 65-75 years of age (162 ng/mL and 6 hours, respectively).^[1][9][43] In clinical studies including geriatric patients receiving tramadol hydrochloride conventional tablets, treatment-limiting adverse GI effects occurred in 30% of patients older than 75 years of age compared with 17% of those younger than 65 years of age, and constipation resulted in discontinuance of treatment in 10% of those older than 75 years of age.^[1]

In clinical trials of tramadol hydrochloride extended-release tablets, 901 patients who received the drug were 65 years of age or older, while 156 patients were 75 years of age or older.^[53] In these studies, the incidence of adverse effects was higher in patients older than 65 years of age compared with younger adults; adverse effects reported more frequently in older adults include constipation, fatigue, weakness, postural hypotension, and dyspepsia.^[53] Tramadol hydrochloride extended-release tablets should be used with caution in patients older than 65 years of age and with even greater caution in those older than 75 years of age.^[53]

In clinical trials of tramadol hydrochloride extended-release capsules, 812 patients who received the drug were 65 years of age or older, while 240 patients were 75 years of age or older.^[59] In these studies, the incidence of adverse effects was higher in patients older than 65 years of age compared with younger adults; adverse effects reported more frequently in older adults include nausea, constipation, somnolence, dizziness, dry mouth, vomiting, asthenia, pruritus, anorexia, sweating, fatigue, weakness, postural hypotension, and dyspepsia.^[59] Tramadol hydrochloride extended-release capsules should be used with great caution in geriatric patients older than 75 years of age.^[59]

Limited data from a study of patients with chronic pain receiving tramadol in fixed combination with acetaminophen indicated that there were no substantial changes in pharmacokinetics of tramadol or acetaminophen in patients 65 years of age and older with normal renal and hepatic function compared with younger adults.^[51]

Pregnancy, Fertility, and Lactation

Pregnancy

Prolonged maternal use of opiate agonists during pregnancy can result in neonatal opiate withdrawal syndrome with manifestations of irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.^[1][53][59] In contrast to adults, the withdrawal syndrome in neonates may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.^[1][53][59] Women who require prolonged opiate agonist therapy during pregnancy should be advised of the risk of neonatal opiate withdrawal syndrome, and availability of appropriate treatment should be ensured.^[1][53][59] The onset, duration, and severity of the syndrome vary depending on the specific opiate agonist used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the neonate.^[1][53][59] Neonatal seizures, neonatal withdrawal syndrome, fetal death, and stillbirth have been reported with tramadol during postmarketing experience.^[1][53][59] The effect of tramadol, if any, on the later growth, development, and functional maturation of the child is unknown.^[1][53][59]

Use of opiates in pregnant women during labor can result in neonatal respiratory depression.^[1][53][59] Use of tramadol is not recommended immediately before or during labor, when other analgesic techniques may be more appropriate.^[1][53][59] Opiate agonists may prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions.^[1][53][59] However, this effect is inconsistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.^[1][53][59] Neonates exposed to opiates during labor should be monitored for excessive sedation and respiratory depression.^[1][53][59] An opiate antagonist must be available for reversal of opiate-induced respiratory depression.^[1][53][59]

Tramadol has been shown to cross the placenta.^[1][53][59] The mean ratio of serum tramadol in the umbilical veins compared with maternal veins was 0.83 for women given tramadol during labor.^[1][53][59]

Analysis of data from the National Birth Defects Prevention Study, a large population-based, case-control study, suggests that therapeutic maternal use of opiate agonists during the period of organogenesis is associated with a low absolute risk of birth defects, including heart defects, spina bifida, and gastroschisis.^[61][62] The manufacturers state that available data regarding use of tramadol in pregnant women are insufficient to establish the risk of major birth defects and spontaneous abortion with the drug.^[1][53][59]

Based on animal data, women of childbearing potential should be advised of the potential for tramadol to cause fetal harm.^[1][53][59]

Although there are no adequate and controlled studies to date in humans, tramadol has been shown to be embryotoxic and fetotoxic in mice, rats, and rabbits at maternally toxic doses 1.4, 0.6, and 3.6 times, respectively, the maximum daily human dosage (120 mg/kg in mice, 25 mg/kg in rats, and 75 mg/kg in rabbits).^[1] Embryo and fetal toxicity consisted mainly of decreased fetal weights, decreased skeletal ossification, and increased supernumerary ribs at maternally toxic dose levels.^[1] Transient delays in developmental or behavioral parameters also were seen in pups from rat dams allowed to deliver.^[1] Embryo and fetal lethality was reported in only one rabbit study, in which rabbits received tramadol hydrochloride 300 mg/kg, a dose that would cause extreme maternal toxicity in rabbits.^[1]

Embryotoxicity and fetotoxicity have been demonstrated in rats when tramadol and acetaminophen were administered in fixed combination at maternally toxic doses of 50 and 434 mg/kg, respectively, or 1.6 times the maximum daily human dosages of these drugs.^[51] Embryonic and fetal toxicity consisted of decreased fetal weights and increased supernumerary ribs.^[51]

Tramadol was not teratogenic in mice, rats, and rabbits at maternally toxic doses 1.4, 0.6, and 3.6 times, respectively, the maximum human daily dosage (120 mg/kg in mice, 25 mg/kg in rats, and 75 mg/kg in rabbits).^[1] No drug-related teratogenic effects were observed in progeny of mice, rats, or rabbits receiving tramadol (up to 140, 80, or 300 mg/kg or 1.7, 1.9, or 14.6 times, respectively, the maximum daily human dosage) by various routes.^[1]

Tramadol and acetaminophen in fixed combination was not teratogenic in rats at a maternally toxic dose of 50 and 434 mg/kg, respectively, or 1.6 times the maximum daily human dosages of these drugs.^[51]

In perinatal and postnatal studies in rats, progeny of dams receiving oral (gavage) tramadol hydrochloride doses of 50 mg/kg or higher had decreased weights, and pup survival was decreased early in lactation at tramadol hydrochloride doses of 80 mg/kg (1.2-1.6 or 1.9-2.6 times, respectively, the maximum human dose).^[1][51] No toxicity was observed for progeny of dams receiving doses of 8, 10, 20, 25, or 40 mg/kg.^[52] Maternal toxicity was observed at all dose levels, but effects on progeny were evident only at higher dose levels where maternal toxicity was more severe.^[52]

Fertility

Long-term use of opiates may reduce fertility in females and males of reproductive potential.^[1][53][59] It is not known whether these effects are reversible.^[1][53][59] (See Cautions: Genitourinary and Endocrine Effects.)

No effects on fertility were observed in male rats receiving oral tramadol hydrochloride doses up to 50 mg/kg or in female rats receiving oral tramadol hydrochloride doses up to 75 mg/kg or 1.2 or 1.8 times, respectively, the maximum daily human dosage based on body surface area.^[1][53][59]

Lactation

Tramadol is distributed into milk.^[1][53] Following a single IV tramadol dose of 100 mg, the cumulative distribution into milk within 16 hours after dosing was 100 mcg of tramadol (0.1% of the maternal dose) and 27 mcg of M1.^[1][53]

Because the safety of tramadol in infants and neonates has not been established, the drug is not recommended for obstetrical preoperative medication or for use in nursing women, including use for post-delivery analgesia.^[1][53] FDA review of available medical literature did not reveal evidence of an increased frequency of adverse effects in nursing infants of women receiving tramadol; however, because the drug is distributed into milk and has similar risks as codeine in ultrarapid metabolizers of CYP2D6 substrates, FDA recommends that tramadol not be used in nursing women.^[705] (See Pharmacogenomics under Cautions: Precautions and Contraindications. Also see Cautions: Precautions and Contraindications, in Codeine Phosphate and Codeine Sulfate 28:08.08.) Infants exposed to tramadol through breast milk should be monitored closely for clinical manifestations of opiate toxicity (e.g., sedation, difficulty breast-feeding or breathing, hypotonia).^[705] If clinical manifestations of opiate toxicity occur, caregivers should seek immediate medical treatment for the infant.^[705]

Symptoms of withdrawal can occur in opiate-dependent infants when maternal administration of opiates is discontinued or breast-feeding is stopped.^[1][53][59]

Tramadol hydrochloride is a synthetic, centrally active analgesic.^{[1][2][3][4][5][15][51][53]} The drug (and its active O-desmethyl metabolite [M1]) acts as an opiate agonist, apparently by selective activity at the µ-receptor.^{[1][2][3][4][5][9][10][11][13][14][16][17][18][19][51][53]} In addition to opiate agonist activity, tramadol inhibits reuptake of certain monoamines (norepinephrine, serotonin), which appears to contribute to the drug's analgesic effect.^{[1][2][3][4][9][10][11][12][13][14][15][16][17][18][19][51][53]} Although the relative contribution of tramadol versus its M1 metabolite to analgesia in humans is unknown, the metabolite is 6 times more potent than the parent drug in producing analgesia in animal models and 200 times more potent in µ-receptor binding.^{[1][3][4][51][53]} The antinociceptic effect of tramadol is antagonized only partially by naloxone in some tests in animals and healthy individuals.^{[1][3][4][10][18][51][53]}

Although the pharmacologic effects of tramadol result in part from agonist activity at opiate receptors,^{[1][2][3][4][5][9][10][11][13][14][16][17][18][19][51]} the drug is not an opium derivative nor a semisynthetic derivative of morphine or thebaine.^[1][21][22] However, because tramadol is an agonist of true opiate receptors, not opiate-like (i.e., opi-oid) receptors,^{[1][2][3][4][5][9][10][11][13][14][16][17][18][19][51]} the drug is classified as an opiate agonist in the AHFS Pharmacologic-Therapeutic Classification^©.^{[27][28][29][30]} (See Chemistry in the Opiate Agonists General Statement 28:08.08.)

Because of the drug's opiate agonist activity at µ-receptors, tramadol also can produce dependence. ^{[1][2][3][4][5][6][8][9][11][16][17][51]} Although tramadol and tramadol in fixed combination with acetaminophen were not originally subject to control under the Federal Controlled Substances Act of 1970 as scheduled drugs, these preparations became subject to such control as schedule IV (C-IV) drugs effective August 18, 2014.^[56] Current data suggest that the abuse potential of tramadol is less than that of morphine or oxycodone but similar to that of propoxyphene.^[56] Tolerance and manifestations of withdrawal also can occur, although such effects are relatively mild compared with those of other opiate agonists.^{[1][3][4][8][51][53]}

Tramadol shares many of the other pharmacologic and toxicologic effects of opiate agonists, including dizziness, somnolence, nausea, constipation, dry mouth, sweating, and pruritus.^{[1][2][3][4][5][7][8][9][11][51][53]} The respiratory depressant effects of the drug are less than those of morphine, and usually are not clinically important at usual oral doses.^{[1][2][5][6][9][11][13][14][17]} At relatively high doses (e.g., those administered parenterally), tramadol can produce respiratory depression,^[1][4][5] and even usual oral doses should be employed cautiously in patients at risk for respiratory depression.^{[1][11][51][53]} At usual oral doses, the drug exhibits minimal cardiovascular effects,^[1][2][4][6] although hypotension, syncope, and tachycardia can occur occasionally.^[1][51]

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Effective August 18, 2014, tramadol hydrochloride preparations are subject to control under the Federal Controlled Substances Act of 1970 as schedule IV (C-IV) drugs.^[56] (See Description.)

\* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

\* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

AHFS Drug Information®. © Copyright, 1959-2024, Selected Revisions September 10, 2024. American Society of Health-System Pharmacists®, 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

This AHFS Drug Information Database is copyrighted by the American Society of Health-System Pharmacists, Inc. (C) 2025, ASHP, Bethesda, Maryland 20814. All Rights Reserved. Duplication must be expressly authorized by ASHP, unless such duplication consists of printing or downloading portions of the data inherent in the program for non-commercial use.

The American Society of Health-System Pharmacists, Inc. represents that the database provided hereunder as formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. makes no representations or warranties, express or implied, including, but not limited to, any implied warranty or merchantability and/or fitness for a particular purpose, with respect to such database and specifically disclaims all such warranties and representations. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the database if provided for informational purposes only. The entire monograph for a drug should be reviewed for a throrough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug in the database. The information contained in the database is not a substitute for medical care or treatment by a licensed health care provider.