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Tramadol: Drug information

Tramadol: Drug information
2024© UpToDate, Inc. and its affiliates and/or licensors. All Rights Reserved.
For additional information see "Tramadol: Patient drug information" and "Tramadol: Pediatric drug information"

For abbreviations, symbols, and age group definitions show table
ALERT: US Boxed Warning
Risk of medication errors:

Ensure accuracy when prescribing, dispensing, and administering tramadol oral solution. Dosing errors due to confusion between mg and mL can result in accidental overdose and death.

Addiction, abuse, and misuse:

Because the use of tramadol exposes patients and other users to the risks of opioid addiction, abuse, and misuse, which can lead to overdose and death, assess each patient's risk prior to prescribing and reassess all patients regularly for the development of these behaviors and conditions.

Opioid analgesic Risk Evaluation and Mitigation Strategy (REMS):

Health care providers are strongly encouraged to complete a REMS-compliant education program and to counsel patients and caregivers on serious risks, safe use, and the importance of reading the Medication Guide with each prescription.

Life-threatening respiratory depression:

Serious, life-threatening, or fatal respiratory depression may occur with use of tramadol, especially during initiation or following a dose increase. To reduce the risk of respiratory depression, proper dosing and titration of tramadol are essential. Instruct patients to swallow tramadol extended release products intact, and not to cut, break, chew, crush, or dissolve to avoid exposure to a potentially fatal dose of tramadol.

Accidental ingestion:

Accidental ingestion of even one dose of tramadol, especially by children, can result in a fatal overdose of tramadol.

Ultra-rapid metabolism of tramadol and other risk factors for life-threatening respiratory depression in children:

Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; in at least 1 case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP450 2D6 polymorphism. Tramadol is contraindicated in children <12 years of age and in children <18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of tramadol in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol.

Neonatal opioid withdrawal syndrome:

If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of neonatal opioid withdraw syndrome (NOWS), which may be life-threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery.

Interactions with drugs affecting cytochrome P450 isoenzymes:

The effects of concomitant use or discontinuation of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol are complex. Use of cytochrome P450 3A4 inducers, 3A4 inhibitors, or 2D6 inhibitors with tramadol requires careful consideration of the effects on the parent drug, tramadol, and the active metabolite, M1.

Risks from concomitant use with benzodiazepines or other CNS depressants:

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of tramadol and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.

Brand Names: US
  • ConZip;
  • Qdolo;
  • Ultram [DSC]
Brand Names: Canada
  • APO-Tramadol;
  • AURO-Tramadol;
  • Durela;
  • JAMP Tramadol;
  • JAMP-traMADol HCl;
  • MAR-Tramadol;
  • Ralivia;
  • SANDOZ Tramadol [DSC];
  • TARO-Tramadol ER;
  • Tridural;
  • Ultram [DSC];
  • Zytram XL
Pharmacologic Category
  • Analgesic, Opioid
Dosing: Adult

Dosage guidance:

Safety: Consider prescribing naloxone for patients with factors associated with an increased risk for overdose, such as history of overdose or substance use disorder, patients with sleep-disordered breathing, higher opioid dosages (≥50 morphine milligram equivalents [MME]/day orally), and/or concomitant benzodiazepine use (Ref).

Pain management, moderate to severe

Pain management, moderate to severe:

Note: Opioids may be part of a comprehensive, multimodal, patient-specific treatment plan for managing pain. Maximize nonopioid analgesia (when appropriate) prior to initiation of opioid analgesia (Ref). Dosing provided is based on typical doses; some patients may require higher or lower doses. Individualize dosing and dosing intervals based on patient-specific factors (eg, severity of pain, comorbidities, degree of opioid experience/tolerance) and titrate to patient-specific treatment goals (eg, improvement in function and quality of life, decrease in pain using a validated pain rating scale). Use the lowest effective dose for the shortest period of time.

Acute pain (eg, postoperative):

Note: For patients who are experiencing acute pain severe enough to require opioids (in addition to appropriate nonopioid analgesia). Long-acting preparations are not recommended for treatment of acute pain in opioid-naive patients (Ref). Some experts avoid the use of tramadol in patients with moderate to severe acute pain due to the wide interpatient variability in metabolism and related incidences of adverse events and unreliable analgesia (Ref).

Immediate release: Oral: Initial: 50 mg every 4 to 6 hours as needed (Ref); if rapid onset of analgesic effect is required, may consider an initial dose of 50 to 100 mg every 4 to 6 hours; some experts suggest that 25 to 50 mg 3 times per day may be sufficient for patients with moderate acute pain (Ref). Increase dose as needed and tolerated to 50 to 100 mg every 4 to 6 hours; maximum daily dose: 400 mg/day (Ref).

Chronic pain (alternative agent):

Note: Opioids, including tramadol, are not the preferred therapy for chronic noncancer pain due to insufficient evidence of benefit and risk of serious harm; nonpharmacologic treatment and nonopioid analgesics are preferred with the exception of pain from sickle cell disease and in end-of-life care. Opioids, including tramadol, should only be considered in patients who experience clinically meaningful improvement in pain and function that outweighs patient safety risks (Ref). The utility of tramadol in patients with chronic pain due to cancer is questionable, especially considering its dual mechanism of action and dose ceiling (Ref).

Opioid-naive patients not currently on tramadol immediate release:

Immediate release: Oral: The ideal dosing regimen has not been established; consider restricting the initial dose to <300 mg tramadol per day (ie, <50 mg morphine equivalents daily) (Ref). An example initial dose is 25 to 50 mg every 6 hours as needed (Ref). The dose may be increased as needed and tolerated to 50 to 100 mg every 4 to 6 hours (maximum: 400 mg/day) (Ref).

Extended release:

Note: Although manufacturer's labeling contains the following directions for initiating ER tramadol products in opioid-naive patients with chronic pain, it is recommended that when starting opioid therapy, treatment be initiated with an IR preparation to more accurately determine the daily opioid requirement and decrease the risk of overdose. Reserve ER opioids for patients who have received IR opioids daily for ≥1 week yet continue to experience severe, continuous pain (Ref).

Initial: Oral: 100 mg once daily; titrate by 100 mg/day increments every 5 days as needed (maximum: 300 mg/day)

Tridural [Canadian product]: Initial: Oral: 100 mg once daily; titrate by 100 mg/day increments every 2 days as needed (maximum: 300 mg/day)

Zytram XL [Canadian product]: Oral: 150 mg once daily; if pain relief is not achieved, may titrate by increasing dosage incrementally with sufficient time to evaluate effect of increased dosage, generally not more often than every 7 days (maximum: 400 mg/day).

Patients currently on tramadol IR tablets for ≥1 week: Calculate 24-hour tramadol IR tablet total dose and initiate total ER daily dose (round dose to the next lowest 100 mg increment); titrate as needed and tolerated to desired effect (maximum: 300 mg/day). In patients who experience breakthrough pain, clinicians may consider the addition of an IR rescue analgesic (eg, NSAID or short-acting weak opioid). Note: Oral solution relative bioavailability compared to ER products has not been established; conversion to ER products should be accompanied by close monitoring of excessive sedation and respiratory depression.

Discontinuation or tapering of therapy: When reducing the dose, discontinuing, or tapering long-term opioid therapy, the dose should be gradually tapered. An optimal tapering schedule has not been established. Individualize tapering based on discussions with patient to minimize withdrawal, while considering patient-specific goals and concerns and the opioid's pharmacokinetics. Proposed initial schedules range from slow (eg, 10% reduction per week or 10% reduction per month depending on duration of long-term therapy) to rapid (eg, 25% to 50% reduction every few days) (Ref). Slower tapers may be appropriate after long-term use (eg, >1 year), whereas more rapid tapers may be appropriate in patients experiencing severe adverse effects. During tapering, patients may be at an increased risk of overdose if they return to their original (or higher) opioid dose or use illicit opioids, due to rapid loss of tolerance; consider prescribing naloxone. Monitor carefully for signs/symptoms of withdrawal. If the patient displays withdrawal symptoms, consider slowing the taper schedule; alterations may include increasing the interval between dose reductions, decreasing amount of daily dose reduction, pausing the taper and restarting when the patient is ready, and/or coadministration of an alpha-2 agonist (eg, clonidine) to blunt autonomic withdrawal symptoms and other adjunctive agents to treat GI symptoms and muscle spasms, as needed. Continue to offer nonopioid analgesics as needed for pain management during the taper (Ref).

Premature ejaculation

Premature ejaculation (alternative agent) (off-label use):

Note: Tramadol may be considered in patients who have failed other therapies (eg, SSRIs, topical anesthetics). Consideration should be given to the risk of substance use disorder and adverse effects associated with opioids (Ref); to promote safe use, regular follow-up to monitor for response, toxicity, and misuse is recommended.

Immediate release: Oral: The ideal dosing regimen has not been established; dosage range studied: 25 to 50 mg administered on demand 1 to 3 hours prior to intercourse (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Altered kidney function (Ref):

CrCl ≥30 mL/minute: Immediate release, extended release: No dosage adjustment necessary.

CrCl <30 mL/minute: Immediate release: Increase dosing interval to every 12 hours; maximum: 200 mg/day. ER formulation should be avoided.

Hemodialysis, intermittent (thrice weekly): Dialyzable (7%):

Immediate release: Lower initial doses and an extended dosing interval (eg, 25 mg twice daily) are recommended (Ref); titrate to response. The manufacturer’s labeling recommends a maximum daily dose of 200 mg/day; however, since a uremic state may lower seizure threshold, some experts recommend not exceeding 50 mg twice daily (Ref). ER formulation should be avoided.

Peritoneal dialysis: Dialyzability unknown (Davison 2014):

Immediate release: Lower initial doses and an extended dosing interval (eg, 25 mg twice daily) are recommended (Ref); titrate to response. Although a maximum daily dose of 200 mg/day has been suggested (Ref), some experts recommend not exceeding 100 mg/day since a uremic state may lower the seizure threshold (Ref). ER formulation should be avoided.

Dosing: Hepatic Impairment: Adult

The hepatic dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Matt Harris, PharmD, MHS, BCPS, FAST; Jeong Park, PharmD, MS, BCTXP, FCCP, FAST; Arun Jesudian, MD; Sasan Sakiani, MD.

Note: Tramadol is a prodrug that requires conversion to the primary active metabolite (O-desmethyl tramadol) in the liver. In patients with hepatic impairment, tramadol is subject to reduced hepatic metabolism, which may result in ineffective pain control (Ref). Dose recommendations for hepatic impairment are based on the usual recommended dose of 50 to 100 mg every 4 to 6 hours for the treatment of acute and chronic pain. Use of the IR formulation is preferred over the ER formulation in patients with hepatic impairment (Ref).

Initial or dose titration in patients with preexisting liver cirrhosis :

Pain management: Moderate to severe:

Acute pain: Immediate release:

Child-Turcotte-Pugh class A: Oral: Initial: 50 mg every 8 hours as needed; may increase to 50 mg every 6 hours based on tolerability and response (maximum: 200 mg/day) (Ref).

Child-Turcotte-Pugh class B: Oral: Initial: 25 mg every 8 to 12 hours as needed; may increase to max 100 mg/day in 2 to 3 divided doses based on tolerability and response (Ref).

Child-Turcotte-Pugh class C: Use is not recommended (Ref).

Chronic pain:

Child-Turcotte-Pugh class A and B: Use of alternative analgesics (opioid or nonopioid) are preferred due to potential decreased tramadol efficacy (Ref).

Child-Turcotte-Pugh class C: Use is not recommended (Ref).

Dosage adjustment in patients with chronic, worsening hepatic function during treatment (eg, progression from Child-Turcotte-Pugh class A to B):

Pain management: Moderate to severe:

New Child-Turcotte-Pugh class A and B: Use of alternative analgesics (opioid or nonopioid) are preferred due to potential decreased tramadol efficacy (Ref).

Progression to Child-Turcotte-Pugh class C: Use is not recommended; use of alternative analgesics (opioid or nonopioid) are preferred due to potential decreased tramadol efficacy (Ref).

Acute worsening of hepatic function (eg, requiring hospitalization): Discontinue tramadol during the acute event; may resume once the acute event has resolved (ie, LFTs have stabilized or returned to baseline) (Ref).

Dosing: Older Adult

Note: Minimize opioid use in older adults unless for the management of severe acute pain. Opioids are associated with an increased risk of falls and inducing or worsening delirium in older adults (Ref).

Elderly >65 years to ≤75 years: Refer to adult dosing; use with caution and initiate at the low end of the dosing range.

Elderly >75 years:

Immediate release: Maximum: 300 mg/day.

Extended release: Use with extreme caution.

Dosing: Pediatric

(For additional information see "Tramadol: Pediatric drug information")

Dosage guidance:

Safety: Due to potential respiratory complications, use is contraindicated in all patients <12 years of age and all pediatric patients undergoing tonsillectomy and/or adenoidectomy (Ref). Avoid use in patients ≥12 years with risk factors that may increase sensitivity to the respiratory depressant effects of tramadol (eg, obesity, ultra-rapid metabolizer, conditions associated with hypoventilation including postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, concomitant use of medications that cause respiratory depression) unless benefits outweigh the risks (Ref).

Assess need and discuss availability of naloxone for emergent treatment of opioid overdose with patient and/or caregiver upon initiating and renewing treatment.

Acute pain, moderate to severe

Acute pain, moderate to severe (excluding postoperative tonsillectomy/adenoidectomy pain): Note: Doses should be titrated to appropriate analgesic effect; use the lowest effective dose for the shortest period of time.

Immediate-release formulations (tablet, oral solution):

Children ≥12 years and Adolescents ≤16 years: Limited data available: Oral: 1 to 2 mg/kg/dose every 4 to 6 hours; maximum dose: 100 mg/dose (adult initial dose range: 25 to 100 mg/dose); maximum daily dose: 8 mg/kg/day not to exceed 400 mg/day (Ref). Note: Due to potential respiratory complications, tramadol is contraindicated in patients <12 years of age and all pediatric patients undergoing tonsillectomy and/or adenoidectomy (Ref).

Adolescents ≥17 years: Oral: 50 to 100 mg every 4 to 6 hours as needed; maximum daily dose: 400 mg/day. For patients not requiring rapid onset of effect, tolerability to adverse effects may be improved by initiating therapy at 25 mg/day and titrating dose by 25 mg every 3 days until 25 mg 4 times daily is reached. Dose may then be increased by 50 mg every 3 days as tolerated to reach 50 mg 4 times daily (Ref).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Children ≥12 years and Adolescents: Immediate-release formulations (tablet, oral solution):

Altered kidney function:

CrCl ≥30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling.

CrCl <30 mL/minute: There are no recommendations in the manufacturer's labeling. In adult patients, increasing dosing interval to every 12 hours is recommended; maximum adult daily dose: 200 mg/day.

Hemodialysis, intermittent: Dialyzable (7%); there are no recommendations in the manufacturer's labeling; in adult patients, decreased dose and extended dosing interval are recommended.

Dosing: Hepatic Impairment: Pediatric

Children ≥12 years and Adolescents: Immediate-release formulations (tablet, oral solution): There are no dosage adjustments provided in the manufacturer's labeling. In adult patients with severe impairment, dose reduction is recommended.

Adverse Reactions (Significant): Considerations
CNS effects

Various CNS effects have been reported in association with tramadol use in clinical trials and case reports. In clinical trials, the most common CNS effects include dizziness, sedated state, drowsiness, headache, and central nervous system stimulation. Less commonly reported CNS adverse effects include euphoria, anxiety, depression, anger, hostility, aggression, lack of concentration, and cognitive dysfunction (Ref). In contrast, improvements in anxiety and depression symptoms have been reported during tramadol use (Ref). Euphoric effects and possible antianxiety and antidepressant effects may contribute to the addiction potential of tramadol (Ref).

Mechanism: Dose-related; tramadol metabolism to active metabolite, M1, may contribute to euphoric effect (Ref).

Risk factors:

• Dose; generally greater with higher doses

• Concurrent use of CNS depressant medications

• CYP2D6 ultra-rapid metabolizers

Constipation

Constipation has been reported in patients taking opioids, including tramadol (Ref).

Mechanism: Dose-related; related to the pharmacologic action (ie, activation of mu opioid receptors in the GI tract resulting in decreased peristalsis, reduced mucosal secretions, and delayed gastric emptying) (Ref).

Onset: Intermediate; occurs within first 4 weeks of therapy (Ref). Minimal to no tolerance to constipation develops with chronic use ((Ref).

Risk factors:

• Dose; generally greater with higher doses

Hyponatremia

Hyponatremia has been reported with tramadol use; many cases have been severe (sodium <120 mmol/L). Some cases have occurred due to the syndrome of inappropriate antidiuretic hormone.

Onset: Varied; most cases have occurred within the first week of initiation.

Risk factors:

• Females >65 years of age may be at higher risk

Respiratory depression

Life-threatening or fatal respiratory depression has occurred with opioids, including tramadol, at therapeutic and supratherapeutic doses in adult and pediatric patients (Ref). Respiratory depression may be reversible with medical intervention (Ref). Tramadol may be associated with less risk of respiratory depression than other opioids in adults (Ref); in pediatric patients, a serious (sometimes fatal) risk of respiratory depression exists with tramadol and is similar to that of opioids such as codeine (Ref).

Mechanism: Dose-related; related to the pharmacologic action (ie, activation of mu opioid receptors in the CNS respiratory center) (Ref).

Onset: Rapid; mean of 8 hours after ingestion (range: 1 to 24 hours); dependent on dose and patient variables (eg, CYP2D6 ultra-rapid metabolizer, kidney impairment) (Ref).

Risk factors:

• Dose; generally greater with higher doses (Ref)

• Age ≥65 years (Ref)

• Cachexia

• Cardiovascular disease (Ref)

• Chronic pulmonary disease (Ref)

• Concurrent use of other psychoactive medications (eg, benzodiazepines or CNS depressants, antipsychotics) (Ref)

• CYP2D6 ultra-rapid metabolizers (adult and pediatric) (Ref)

• Debilitation

• Depression (or other concurrent psychiatric illness) (Ref)

• Kidney or liver impairment (Ref)

• Substance use disorder (Ref)

• Pediatric:

• Age <12 years of age (Ref)

• Age ≥12 years with comorbid conditions like obesity, obstructive sleep apnea, or severe lung disease, which may increase the risk of serious breathing problem (Ref)

Seizures

Seizure has been reported after therapeutic and supratherapeutic doses of tramadol (Ref). Seizures typically present as a single generalized tonic-clonic episode lasting <5 minutes (Ref); although, recurrent seizures have been reported (Ref).

Mechanism: Dose-related. Mechanism not fully elucidated; may be related to excessive serotonergic activity (Ref), opioid-dependent GABA receptor inhibition (Ref), and/or opioid-receptor dependent histamine release (Ref).

Onset: Rapid; occurs within 4 to 6 hours of ingestion (Ref).

Risk factors:

• Dose; generally greater with higher doses (Ref)

• Concurrent medications: Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs) and other tricyclic compounds (eg, cyclobenzaprine, promethazine), other opioids, monoamine oxidase inhibitors (MAOIs), anorectics, neuroleptics, drugs that reduce the seizure threshold, and/or drugs that impair metabolism of tramadol (eg, CYP2D6 and 3A4 inhibitors)

• CYP2D6 poor metabolizers (Ref)

• History of seizure disorder

• Patients otherwise at risk for seizures (ie, alcohol withdrawal, CNS infections, head trauma)

Serotonin syndrome

Life-threatening serotonin syndrome has been reported after therapeutic and supratherapeutic doses of tramadol (Ref). Risk is increased when tramadol is administered in combination with agents that increase its plasma concentrations (eg, CYP2D6 and CYP3A4 inhibitors) and with other serotonergic agents. However, it has been reported after tramadol monotherapy; more often observed in the setting of overdose (Ref). Serotonin syndrome may be reversible with medical intervention (Ref).

Mechanism: Excessive serotonin concentrations at the synaptic cleft and/or inhibition of tramadol metabolism leading to increased tramadol concentrations (Ref).

Onset: Varied; may occur within several hours to days after administration or may present later.

Risk factors:

• Concurrent use of serotonergic medications: Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), triptans, etc. (Ref)

• Concurrent use of CYP2D6 and/or CYP3A4 inhibitors (Ref)

• CYP2D6 poor metabolizers (Ref)

• Age >65 years (Ref)

Withdrawal syndrome

Physical dependence, manifesting as a withdrawal syndrome, has been observed after abrupt discontinuation of tramadol (Ref). Reported symptoms are consistent with both opioid and serotonin withdrawal (Ref). Withdrawal symptoms may occur after several days or longer therapy durations. Withdrawal symptoms usually resolve within 2 to 7 days (Ref).

Mechanism: Withdrawal; autonomic hyperexcitability in the absence of opioid agonist suppressive effects (Ref); reduced availability of serotonin (Ref).

Onset: Rapid; symptom onset typically occurs within 24 hours of discontinuing tramadol therapy and usually resolves within 2 to 7 days (Ref).

Risk factors:

• Abrupt discontinuation of tramadol in physically dependent patients

• Concurrent use of opioid mixed agonist/antagonists, opioid partial agonists, or naloxone (Ref)

• Duration of use (potential risk factor) (Ref)

• Higher doses (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Gastrointestinal: Constipation (9% to 21%) (table 1), dyspepsia, nausea (15% to 26%), xerostomia (5% to 13%)

Tramadol: Adverse Reaction: Constipation

Drug (Tramadol)

Placebo

Dose

Dosage Form

Number of Patients (Tramadol)

Number of Patients (Placebo)

21%

4%

300 mg

Extended-release tablets

400

406

21%

4%

300 mg

Extended-release capsules

1,054

646

17%

4%

200 mg

Extended-release tablets

400

406

14%

4%

200 mg

Extended-release capsules

434

646

12%

4%

100 mg

Extended-release tablets

403

406

9%

4%

100 mg

Extended-release capsules

429

646

Nervous system: Dizziness (10% to 23%) (table 2), drowsiness (7% to 16%) (table 3), headache (12% to 23%) (table 4), vertigo

Tramadol: Adverse Reaction: Dizziness

Drug (Tramadol)

Placebo

Dose

Dosage Form

Number of Patients (Tramadol)

Number of Patients (Placebo)

23%

7%

300 mg

Extended-release tablets

400

406

20%

7%

200 mg

Extended-release tablets

400

406

16%

7%

100 mg

Extended-release tablets

403

406

14%

5%

300 mg

Extended-release capsules

1,054

646

12%

5%

200 mg

Extended-release capsules

434

646

10%

5%

100 mg

Extended-release capsules

429

646

Tramadol: Adverse Reaction: Drowsiness

Drug (Tramadol)

Placebo

Dose

Dosage Form

Number of Patients (Tramadol)

Number of Patients (Placebo)

16%

4%

300 mg

Extended-release capsules

1,054

646

14%

4%

200 mg

Extended-release capsules

434

646

12%

4%

100 mg

Extended-release capsules

429

646

11%

2%

200 mg

Extended-release tablets

400

406

8%

2%

100 mg

Extended-release tablets

403

406

7%

2%

300 mg

Extended-release tablets

400

406

Tramadol: Adverse Reaction: Headache

Drug (Tramadol)

Placebo

Dose

Dosage Form

Number of Patients (Tramadol)

Number of Patients (Placebo)

23%

20%

100 mg

Extended-release capsules

429

646

22%

20%

200 mg

Extended-release capsules

434

646

19%

20%

300 mg

Extended-release capsules

1,054

646

16%

11%

200 mg

Extended-release tablets

400

406

12%

11%

300 mg

Extended-release tablets

400

406

12%

11%

100 mg

Extended-release tablets

403

406

1% to 10%:

Cardiovascular: Chest pain (1% to 5%), flushing (8% to 10%), hypertension (1% to 5%), orthostatic hypotension (≤4%), peripheral edema (<5%), vasodilation (1% to 5%)

Dermatologic: Dermatitis (1% to 5%), diaphoresis (2% to 7%), pruritus (3% to 9%), skin rash (1% to 5%)

Endocrine & metabolic: Hot flash (1% to 5%), hyperglycemia (1% to 5%), menopausal symptoms (1% to 5%), weight loss (1% to 5%)

Gastrointestinal: Abdominal pain (1% to 5%; upper abdominal pain: 1% to 5%), anorexia (1% to 6%), decreased appetite (1% to 5%), diarrhea (7% to 9%), flatulence (<5%), vomiting (5% to 10%)

Genitourinary: Pelvic pain (1% to 5%), prostatic disease (1% to 5%), urinary frequency (<5%), urinary retention (<5%), urinary tract infection (1% to 5%)

Nervous system: Agitation (<5%), anxiety (1% to 5%), apathy (1% to 5%), asthenia (4% to 9%), ataxia (1% to 5%), chills (1% to 5%), confusion (1% to 5%), depersonalization (1% to 5%), depression (1% to 5%), euphoria (<5%), falling (1% to 5%), hypertonia (1% to 5%), hypoesthesia (1% to 5%), insomnia (5% to 9%), lethargy (1% to 5%), malaise (<5%), nervousness (1% to 5%), paresthesia (1% to 5%), restlessness (1% to 5%), rigors (1% to 5%), sleep disorder (<5%), tremor (<5%), withdrawal syndrome (<5%)

Neuromuscular & skeletal: Arthralgia (1% to 5%), back pain (1% to 5%), increased creatine phosphokinase in blood specimen (1% to 5%), limb pain (1% to 5%), myalgia (<5%), neck pain (1% to 5%)

Ophthalmic: Blurred vision (1% to 5%), miosis (1% to 5%)

Respiratory: Bronchitis (1% to 5%), cough (1% to 5%), dyspnea (1% to 5%), flu-like symptoms (1% to 5%), nasal congestion (1% to 5%), nasopharyngitis (1% to 5%), pharyngitis (1% to 5%), rhinitis (1% to 5%), rhinorrhea (1% to 5%), sinusitis (1% to 5%), sneezing (1% to 5%), upper respiratory tract infection (1% to 5%)

Miscellaneous: Accidental injury (<5%), fever (1% to 5%)

<1%:

Cardiovascular: Acute myocardial infarction, hypotension, ischemic heart disease, lower extremity edema, palpitations, peripheral ischemia, syncope, tachycardia

Dermatologic: Cellulitis, cold and clammy skin, ecchymoses, night sweats, piloerection, skin vesicle, Stevens-Johnson syndrome (Mockenhaupt 2008), toxic epidermal necrolysis (Mockenhaupt 2008), urticaria

Endocrine & metabolic: Decreased libido, menstrual disease

Gastrointestinal: Appendicitis, cholecystitis, cholelithiasis, dysgeusia, gastroenteritis, pancreatitis

Genitourinary: Cystitis, dysuria, hematuria

Hematologic & oncologic: Anemia, bruise

Hepatic: Increased gamma-glutamyl transferase

Nervous system: Abnormal dreams, cognitive dysfunction, disorientation, emotional lability, hallucination, irritability, lack of concentration, migraine, sedated state, seizure (Memarian 2018), serotonin syndrome (Shakoor 2014), suicidal tendencies, yawning

Neuromuscular & skeletal: Gout, hyperkinetic muscle activity, joint stiffness, lower limb cramp, muscle cramps, muscle spasm, muscle twitching, neck stiffness

Otic: Otitis, tinnitus

Respiratory: Pneumonia

Frequency not defined:

Hypersensitivity: Angioedema

Neuromuscular & skeletal: Muscle spasticity

Respiratory: Bronchospasm

Postmarketing:

Cardiovascular: Prolonged QT interval on ECG, pulmonary embolism, torsades de pointes

Dermatologic: Erythema multiforme (Sanchez-Gonzalez 2020)

Endocrine & metabolic: Adrenocortical insufficiency (Debono 2011), hypoglycemia (within 30 days of initiation [Fournier 2015, Odonkor 2016]; may occur more often in patients with predisposing risk factors [eg, diabetes] and may result in hospitalization), hyponatremia

Gastrointestinal: Gastrointestinal hemorrhage, stomatitis

Genitourinary: Proteinuria

Hepatic: Hepatic failure, hepatitis

Hypersensitivity: Anaphylaxis (<0.1%) (Mori 2015)

Nervous system: Allodynia (opioid-induced hyperalgesia) (FDA Safety Alert, April 14, 2023), delirium (Agrawal 2009, Kunig 2006)

Neuromuscular & skeletal: Femoral neck fracture (Wei 2020)

Ophthalmic: Cataract, mydriasis (Makris 2012)

Otic: Deafness

Respiratory: Pulmonary edema, respiratory depression (Hassanian-Moghaddam 2013)

Contraindications

Hypersensitivity (eg, anaphylaxis) to tramadol, opioids, or any component of the formulation; pediatric patients <12 years of age; postoperative management in pediatric patients <18 years of age who have undergone tonsillectomy and/or adenoidectomy; significant respiratory depression; acute or severe bronchial asthma in the absence of appropriately monitored settings and/or resuscitative equipment; GI obstruction, including paralytic ileus (known or suspected); concomitant use with or within 14 days following monoamine oxidase inhibitor therapy.

Canadian products: Additional contraindications (not in US labeling): (Note: Contraindications may differ between product labeling; refer also to product labeling): Severe renal impairment (CrCl <30 mL/minute), severe hepatic impairment (Child-Pugh class C); mild, intermittent, or short-duration pain that can be managed with other pain medication; management of perioperative pain; status asthmaticus, chronic obstructive airway, acute respiratory depression, hypercapnia, cor pulmonale, delirium tremens, seizure disorder, severe CNS depression, increased cerebrospinal or intracranial pressure, brain tumor, head injury, suspected surgical abdomen (eg, acute appendicitis or pancreatitis); acute intoxication with ethanol, hypnotics, centrally acting analgesics, opioids, or psychotropic drugs; breastfeeding, pregnancy; use during labor and delivery.

Warnings/Precautions

Concerns related to adverse effects:

• Hyperalgesia: Opioid-induced hyperalgesia (OIH) has occurred with short-term and prolonged use of opioid analgesics. Symptoms may include increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily nonpainful stimuli; symptoms may be suggestive of OIH if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior. Consider decreasing the current opioid dose or opioid rotation in patients who experience OIH.

• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute myocardial infarction [MI]), or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Monitor for symptoms of hypotension following initiation or dose titration. Avoid use in patients with circulatory shock.

Disease-related concerns:

• Abdominal conditions: May obscure diagnosis or clinical course of patients with acute abdominal conditions.

• Adrenocortical insufficiency: Use with caution in patients with adrenal insufficiency, including Addison disease. Long-term opioid use may cause secondary hypogonadism, which may lead to mood disorders and osteoporosis (Brennan 2013).

• Biliary tract impairment: Use caution in patients with biliary tract dysfunction or acute pancreatitis; opioids may cause spasm of the sphincter of Oddi.

• CNS depression/coma: Avoid use in patients with impaired consciousness or coma as these patients are susceptible to intracranial effects of CO2 retention.

• Diabetes: Use with caution in patients with diabetes; tramadol may cause hypoglycemia.

• Delirium tremens: Use with caution in patients with delirium tremens.

• Head trauma: Use with extreme caution in patients with head injury, intracranial lesions, or elevated intracranial pressure (ICP); exaggerated elevation of ICP may occur.

• Hepatic impairment: Use with caution; dosage adjustments may be required. ER formulations should not be used in severe hepatic impairment (Child-Pugh class C).

• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, posttraumatic stress disorder) due to potential increased risk for opioid use disorder and overdose; more frequent monitoring is recommended (CDC [Dowell 2022]).

• Obesity: Use with caution in patients who are morbidly obese.

• Prostatic hyperplasia/urinary stricture: Use with caution in patients with prostatic hyperplasia and/or urinary stricture.

• Psychosis: Use with caution in patients with toxic psychosis.

• Renal impairment: Use with caution; reduce dosage of IR formulations in patients with severe renal impairment; ER formulations should be avoided in severe renal impairment.

• Respiratory disease: Use with caution and monitor for respiratory depression in patients with significant chronic obstructive pulmonary disease or cor pulmonale, and those with a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression, particularly when initiating and titrating therapy; critical respiratory depression may occur, even at therapeutic dosages. Consider the use of alternative nonopioid analgesics in these patients.

• Sleep-related disorders: Use with caution in patients with sleep-related disorders, including sleep apnea, due to increased risk for respiratory and CNS depression. Monitor carefully and titrate dosage cautiously in patients with mild sleep-disordered breathing. Avoid opioids in patients with moderate to severe sleep-disordered breathing (CDC [Dowell 2022]).

• Suicide risk: Avoid use in patients who are suicidal; use with caution in patients taking tranquilizers and/or antidepressants, or those with an emotional disturbance including depression. Consider the use of alternative nonopioid analgesics in these patients.

• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.

Special populations:

• CYP2D6 "poor metabolizers": Poor metabolizers have decreased metabolism of tramadol to its active metabolite, which may diminish analgesia; avoid the use of tramadol and consider alternatives that are not metabolized by CYP2D6 (CPIC [Crews 2021]).

• CYP2D6 "ultrarapid metabolizers": Ultrarapid metabolizers have increased metabolism of tramadol to its active metabolite, which may increase the risk of toxicity; avoid the use of tramadol and consider alternatives that are not metabolized by CYP2D6 (CPIC [Crews 2021]). The occurrence of this phenotype is seen in ~1% to 2% of East Asian patients (Chinese, Japanese, Korean), 1% to 10% of Caucasian patients, 3% to 4% of Black patients, and may be >10% in certain racial/ethnic groups (ie, Oceanian, Northern African, Middle Eastern, Ashkenazi Jewish, and Puerto Rican patients). Deaths have also occurred in breastfeeding infants after being exposed to high concentrations of morphine because the mothers were ultrarapid metabolizers of codeine.

• Older adult: Use opioids with caution in older adults; may be more sensitive to adverse effects. Clearance may also be reduced in older adults (with or without renal impairment) resulting in a narrow therapeutic window and increased adverse effects. Monitor closely for adverse effects associated with opioid therapy (eg, respiratory and CNS depression, falls, cognitive impairment, constipation) (CDC [Dowell 2022]). Consider the use of alternative nonopioid analgesics in these patients when possible.

• Pediatric: Respiratory depression:Risk factors include conditions associated with hypoventilation, such as postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, and concomitant use of other medications that cause respiratory depression.

Other warnings/precautions:

• Abuse/misuse/diversion: Use with caution in patients with a history of substance abuse disorder; potential for drug dependency exists. Other factors associated with increased risk for misuse include concomitant depression or other mental health conditions, higher opioid dosages, or taking other CNS depressants. Consider offering naloxone prescriptions in patients with an increased risk for overdose, such as history of overdose or substance use disorder, higher opioid dosages (≥50 morphine milligram equivalents [MME]/day orally), concomitant benzodiazepine use, and patients at risk for returning to a high dose after losing tolerance (CDC [Dowell 2022]).

• Appropriate use: Outpatient setting: Opioids should not be used as first-line therapy for acute (<1-month duration), subacute (1- to 3-month duration), or chronic pain (>3-month duration [outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment]). Preferred management includes nonpharmacologic therapy and nonopioid therapy (eg, nonsteroidal anti-inflammatory drugs, acetaminophen, certain antiseizure medications, and antidepressants) as appropriate for the specific condition. If opioid therapy is initiated, it should be combined with nonpharmacologic and nonopioid therapy, as appropriate. Prior to initiation, known risks and realistic benefits of opioid therapy should be discussed with the patient. Therapy should be initiated at the lowest effective dosage using IR opioids (instead of ER/long-acting opioids). For the treatment of acute pain, therapy should only be given for the expected duration of pain severe enough to require opioids and prescribed as needed (not scheduled). For the treatment of subacute and chronic pain, realistic treatment goals for pain/function should be established, including consideration for discontinuation if benefits do not outweigh risks. Therapy should be continued only if clinically meaningful improvement in pain/function outweighs risks. Risk to patients increases with higher opioid dosages. Dosages ≥50 MME/day are likely to not have increased benefit to pain relief or function relative to overall risk to patients; before increasing dosage to ≥50 MME/day, readdress pain and reassess evidence of individual benefits and risks (CDC [Dowell 2022]).

• Naloxone access: Discuss the availability of naloxone with all patients who are prescribed opioid analgesics, as well as their caregivers, and consider prescribing it to patients who are at increased risk of opioid overdose. These include patients who are also taking benzodiazepines or other CNS depressants, have an opioid use disorder (OUD) (current or history of), have experienced opioid-induced respiratory depression/opioid overdose, have a history of a substance use disorder, or have higher opioid dosages (≥50 MME/day orally) (CDC [Dowell 2022]). Additionally, health care providers should consider prescribing naloxone to patients prescribed medications to treat OUD; patients at risk of opioid overdose even if they are not taking an opioid analgesic or medication to treat OUD; and patients taking opioids, including methadone or buprenorphine for OUD, if they have household members, including children, or other close contacts at risk for accidental ingestion or opioid overdose. Inform patients and caregivers on options for obtaining naloxone (eg, by prescription, directly from a pharmacist, a community-based program) as permitted by state dispensing and prescribing guidelines. Educate patients and caregivers on how to recognize respiratory depression, proper administration of naloxone, and getting emergency help.

• Optimal regimen: An opioid-containing analgesic regimen should be tailored to each patient's needs and based upon the type of pain being treated (acute versus chronic), the route of administration, degree of tolerance for opioids (naive versus chronic user), age, weight, and medical condition. The optimal analgesic dose varies widely among patients; doses should be titrated to pain relief/prevention.

• Surgery: Opioids decrease bowel motility; monitor for decrease bowel motility in postoperative patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.

Warnings: Additional Pediatric Considerations

Due to potential respiratory complications, use is contraindicated in all patients <12 years of age and all pediatric patients undergoing tonsillectomy and/or adenoidectomy (FDA 2015; FDA 2017; manufacturer's labeling). Avoid use in patients ≥12 years with risk factors that may increase sensitivity to the respiratory depressant effects of tramadol (eg, obesity, ultra-rapid metabolizer, conditions associated with hypoventilation including postoperative status, obstructive sleep apnea, obesity, severe pulmonary disease, neuromuscular disease, concomitant use of medications that cause respiratory depression) unless benefits outweigh the risks (manufacturer's labeling).

Dosage Forms Considerations

ConZip extended release capsules are formulated as a biphasic product, providing immediate and extended release components:

100 mg: 25 mg (immediate release) and 75 mg (extended release)

200 mg: 50 mg (immediate release) and 150 mg (extended release)

300 mg: 50 mg (immediate release) and 250 mg (extended release)

EnovaRX-Tramadol and Active-Tramadol creams are compounded from kits. Refer to manufacturer’s labeling for compounding instructions.

Synapryn FusePaq is a compounding kit for the preparation of an oral suspension. Refer to manufacturer's labeling for compounding instructions.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule Extended Release 24 Hour, Oral, as hydrochloride:

ConZip: 100 mg, 200 mg, 300 mg [contains fd&c blue #2 (indigo carm) aluminum lake, quinoline (d&c yellow #10) aluminum lake]

Generic: 100 mg, 150 mg [DSC], 200 mg, 300 mg

Solution, Oral, as hydrochloride:

Qdolo: 5 mg/mL (473 mL) [contains propylene glycol, sodium benzoate; grape flavor]

Generic: 5 mg/mL (5 mL, 473 mL)

Tablet, Oral, as hydrochloride:

Ultram: 50 mg [DSC] [scored; contains corn starch]

Generic: 25 mg, 50 mg, 100 mg

Tablet Extended Release 24 Hour, Oral, as hydrochloride:

Generic: 100 mg, 200 mg, 300 mg

Generic Equivalent Available: US

Yes

Pricing: US

Capsule ER 24 Hour Therapy Pack (ConZip Oral)

100 mg (per each): $14.77

200 mg (per each): $19.35

300 mg (per each): $26.77

Capsule ER 24 Hour Therapy Pack (traMADol HCl (ER Biphasic) Oral)

100 mg (per each): $9.64

200 mg (per each): $12.64

300 mg (per each): $17.48

Solution (Qdolo Oral)

5 mg/mL (per mL): $1.48

Solution (traMADol HCl Oral)

5 mg/mL (per mL): $2.38

Tablet, 24-hour (traMADol HCl (ER Biphasic) Oral)

100 mg (per each): $4.71

200 mg (per each): $7.78

300 mg (per each): $10.86

Tablet, 24-hour (traMADol HCl ER Oral)

100 mg (per each): $3.64

200 mg (per each): $6.02

300 mg (per each): $10.14

Tablets (traMADol HCl Oral)

25 mg (per each): $4.89

50 mg (per each): $0.17 - $1.80

100 mg (per each): $1.93

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule Extended Release 24 Hour, Oral, as hydrochloride:

Durela: 100 mg, 200 mg, 300 mg [contains fd&c blue #2 (indigo carm) aluminum lake, quinoline (d&c yellow #10) aluminum lake]

Tablet, Oral, as hydrochloride:

Ultram: 50 mg [DSC]

Generic: 50 mg

Tablet Extended Release 24 Hour, Oral:

Zytram XL: 75 mg [contains fd&c blue #2 (indigotine,indigo carmine)]

Zytram XL: 150 mg, 400 mg

Tablet Extended Release 24 Hour, Oral, as hydrochloride:

Ralivia: 100 mg, 200 mg, 300 mg

Tridural: 100 mg, 200 mg, 300 mg

Zytram XL: 100 mg, 200 mg, 300 mg

Generic: 100 mg, 200 mg, 300 mg

Controlled Substance

C-IV

Administration: Adult

Oral:

Immediate release: Administer without regard to meals. Measure oral solution with a calibrated oral syringe or other oral dosing device with metric units of measure (do not use household teaspoons or tablespoons); ensure accurate dosing between mg and mL.

Extended release: Swallow whole; do not crush, chew, dissolve, or split.

Capsule: Administer without regard to meals.

Tablet: Administer without regard to meals but administer in a consistent manner of either with or without meals.

Canadian products:

Durela, Ralivia, Zytram XL: Administer without regard to meals.

Tridural: Administer once daily with breakfast.

Bariatric surgery:

Capsule and tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. ER capsule should be swallowed whole. Do not crush, chew, dissolve, or split as this may result in rapid release and a potentially fatal dose of tramadol. IR tablet formulation is available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, clinicians are advised to monitor closely for adverse effects and withdrawal symptoms after bariatric surgery. Oral morphine has been shown to have significantly increased Cmax and decreased Tmax in the immediate period (1 to 2 weeks) and long-term (6 months) period after bariatric surgery.

Administration: Pediatric

Oral:

Immediate-release formulations (tablet, oral solution): May administer with or without food. Measure oral solution with a calibrated oral syringe or other oral dosing device with metric units of measure (do not use household teaspoons or tablespoons).

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

ConZip: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/022370s025lbl.pdf#page=37

Qdolo: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/214044s000lbl.pdf#page=27

Ultram: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/020281s040lbl.pdf#page=4

Ultram ER: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021692s015lbl.pdf#page=36

Use: Labeled Indications

Pain management:

Extended release: Management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Immediate release: Management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.

Limitations of use: Because of the risks of substance use disorder, abuse, and misuse with opioids, which may occur at any dosage or duration, reserve tramadol for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) have not been tolerated or are not expected to be tolerated or have not provided adequate analgesia or are not expected to provide adequate analgesia. IR formulations are not intended to be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. Tramadol ER is not indicated as an as-needed analgesic.

Use: Off-Label: Adult

Premature ejaculation

Medication Safety Issues
Sound-alike/look-alike issues:

TraMADol may be confused with tapentadol, Toradol Trandate, traZODone, Voltaren

Ryzolt may be confused with Rydapt

Ultram may be confused with lithium, Ultane, Ultracet, Voltaren

High alert medication:

The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes (opioids, all formulations and routes of administration) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Acute Care, Community/Ambulatory Care, and Long-Term Care Settings).

Older Adult: High-Risk Medication:

Beers Criteria: Tramadol is identified in the Beers Criteria as a potentially inappropriate medication to be used with caution in patients 65 years and older due to the potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium concentration closely when initiating or adjusting the dose in older adults (Beers Criteria [AGS 2023]).

Pediatric patients: High-risk medication:

KIDs List: Tramadol, when used in pediatric patients <18 years of age, is identified on the Key Potentially Inappropriate Drugs in Pediatrics (KIDs) list and should be used with caution due to risk of respiratory depression unless pharmacogenetic testing completed (weak recommendation; low quality of evidence) (PPA [Meyers 2020]).

International issues:

Theradol [Netherlands] may be confused with Foradil brand name for formoterol [US, Canada, and multiple international markets], Terazol brand name for terconazole [US and Canada], and Toradol brand name for ketorolac [Canada and multiple international markets]

Trexol [Mexico] may be confused with Trexall brand name for methotrexate [US]; Truxal brand name for chlorprothixene [multiple international markets]

Metabolism/Transport Effects

Substrate of CYP2B6 (minor), CYP2D6 (major), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.

Agents with Clinically Relevant Anticholinergic Effects: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor therapy

Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Almotriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Alvimopan: Opioid Agonists may enhance the adverse/toxic effect of Alvimopan. This is most notable for patients receiving long-term (i.e., more than 7 days) opiates prior to alvimopan initiation. Management: Alvimopan is contraindicated in patients receiving therapeutic doses of opioids for more than 7 consecutive days immediately prior to alvimopan initiation. Risk D: Consider therapy modification

Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: Monitor therapy

Amphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapy

Amphetamines: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability). Initiate amphetamines at lower doses, monitor frequently, and adjust doses as needed. Risk C: Monitor therapy

Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Artemether and Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

BuPROPion: May enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor therapy

BusPIRone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

CarBAMazepine: TraMADol may enhance the CNS depressant effect of CarBAMazepine. TraMADol may diminish the therapeutic effect of CarBAMazepine. CarBAMazepine may decrease the serum concentration of TraMADol. Risk X: Avoid combination

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CNS Depressants: May enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

CYP2D6 Inhibitors (Moderate): May decrease serum concentrations of the active metabolite(s) of TraMADol. CYP2D6 Inhibitors (Moderate) may increase the serum concentration of TraMADol. Risk C: Monitor therapy

CYP2D6 Inhibitors (Strong): May decrease serum concentrations of the active metabolite(s) of TraMADol. CYP2D6 Inhibitors (Strong) may increase the serum concentration of TraMADol. Risk C: Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of TraMADol. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of TraMADol. Risk C: Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase serum concentrations of the active metabolite(s) of TraMADol. CYP3A4 Inhibitors (Moderate) may increase the serum concentration of TraMADol. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of TraMADol. CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraMADol. Risk C: Monitor therapy

Dapoxetine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Risk X: Avoid combination

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Desmopressin: Opioid Agonists may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy

DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider therapy modification

Dexmethylphenidate-Methylphenidate: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Dextromethorphan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Digoxin: TraMADol may increase the serum concentration of Digoxin. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy

DroPERidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

DULoxetine: May enhance the adverse/toxic effect of TraMADol. The risk for serotonin syndrome/serotonin toxicity and seizures may be increased with this combination. DULoxetine may diminish the therapeutic effect of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes), reduced tramadol effectiveness and seizures if these agents are combined. Risk C: Monitor therapy

Eletriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination

Ergot Derivatives: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider therapy modification

Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy

Gepirone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy

Herbal Products with Glucose Lowering Effects: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider therapy modification

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Risk C: Monitor therapy

Iobenguane Radiopharmaceutical Products: TraMADol may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer tramadol until at least 7 days after each iobenguane dose. Risk X: Avoid combination

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification

Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Linezolid: May enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Risk D: Consider therapy modification

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lorcaserin (Withdrawn From US Market): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Loxapine: CNS Depressants may enhance the CNS depressant effect of Loxapine. Risk D: Consider therapy modification

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Mavorixafor: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Methylene Blue: May enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Risk D: Consider therapy modification

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Metoclopramide: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Consider monitoring for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors (Antidepressant): May enhance the adverse/toxic effect of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased.. Risk X: Avoid combination

Monoamine Oxidase Inhibitors (Type B): Serotonergic Opioids (High Risk) may enhance the serotonergic effect of Monoamine Oxidase Inhibitors (Type B). This could result in serotonin syndrome. Risk X: Avoid combination

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Nalfurafine: Opioid Agonists may enhance the adverse/toxic effect of Nalfurafine. Opioid Agonists may diminish the therapeutic effect of Nalfurafine. Risk C: Monitor therapy

Nalmefene: May diminish the therapeutic effect of Opioid Agonists. Management: Avoid the concomitant use of oral nalmefene and opioid agonists. Discontinue oral nalmefene 1 week prior to any anticipated use of opioid agonists. If combined, larger doses of opioid agonists will likely be required. Risk D: Consider therapy modification

Naltrexone: May diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid combination

Nefazodone: May enhance the adverse/toxic effect of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Nefazodone may increase the serum concentration of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes), seizures, and tramadol adverse effects when these agents are combined. Risk C: Monitor therapy

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Ondansetron: May enhance the serotonergic effect of TraMADol. This could result in serotonin syndrome. Ondansetron may diminish the therapeutic effect of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and diminished tramadol efficacy when these agents are combined. Risk C: Monitor therapy

Opioids (Mixed Agonist / Antagonist): May diminish the analgesic effect of Opioid Agonists. Management: Seek alternatives to mixed agonist/antagonist opioids in patients receiving pure opioid agonists, and monitor for symptoms of therapeutic failure/high dose requirements (or withdrawal in opioid-dependent patients) if patients receive these combinations. Risk X: Avoid combination

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect of Oxitriptan. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Ozanimod: May enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Risk C: Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

PHENobarbital: May enhance the CNS depressant effect of TraMADol. PHENobarbital may decrease the serum concentration of TraMADol. Management: Avoid use of tramadol and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a strong CYP3A4 inducer, monitor for decreased tramadol efficacy and withdrawal if combined. Risk D: Consider therapy modification

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Polyethylene Glycol-Electrolyte Solution: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Risk C: Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Primidone: May enhance the CNS depressant effect of TraMADol. Primidone may decrease the serum concentration of TraMADol. Management: Avoid use of tramadol and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a strong CYP3A4 inducer, monitor for decreased tramadol efficacy and withdrawal if combined. Risk D: Consider therapy modification

Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapy

Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy

Samidorphan: May diminish the therapeutic effect of Opioid Agonists. Risk X: Avoid combination

Selective Serotonin Reuptake Inhibitors: TraMADol may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and seizures when these agents are combined. Risk C: Monitor therapy

Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): May enhance the adverse/toxic effect of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may diminish the therapeutic effect of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes), seizures, and decreased tramadol efficacy when these agents are combined. Risk C: Monitor therapy

Serotonergic Agents (High Risk, Miscellaneous): Serotonergic Opioids (High Risk) may enhance the serotonergic effect of Serotonergic Agents (High Risk, Miscellaneous). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) if these agents are combined. Risk C: Monitor therapy

Serotonergic Non-Opioid CNS Depressants: May enhance the CNS depressant effect of Serotonergic Opioids (High Risk). Serotonergic Non-Opioid CNS Depressants may enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider therapy modification

Serotonergic Opioids (High Risk): May enhance the CNS depressant effect of TraMADol. Serotonergic Opioids (High Risk) may enhance the serotonergic effect of TraMADol. This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider therapy modification

Serotonin 5-HT1D Receptor Agonists (Triptans): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: May enhance the adverse/toxic effect of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and seizures when these agents are combined. Risk C: Monitor therapy

Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect of Sincalide. Management: Consider discontinuing drugs that may affect gallbladder motility prior to the use of sincalide to stimulate gallbladder contraction. Risk D: Consider therapy modification

Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor therapy

Somatostatin Analogs: Opioid Agonists may diminish the analgesic effect of Somatostatin Analogs. Opioid Agonists may enhance the analgesic effect of Somatostatin Analogs. Risk C: Monitor therapy

St John's Wort: May enhance the serotonergic effect of TraMADol. This could result in serotonin syndrome. St John's Wort may decrease the serum concentration of TraMADol. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and reduced tramadol effects (including withdrawal symptoms) when combined. Monitor for increased tramadol effects if St John's wort is discontinued. Risk C: Monitor therapy

Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Risk C: Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Syrian Rue: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Tricyclic Antidepressants: May enhance the CNS depressant effect of Serotonergic Opioids (High Risk). Serotonergic Opioids (High Risk) may enhance the serotonergic effect of Tricyclic Antidepressants. This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider therapy modification

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Vitamin K Antagonists (eg, warfarin): TraMADol may enhance the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Zuranolone: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider therapy modification

Reproductive Considerations

Chronic opioid use may cause hypogonadism and hyperprolactinemia which may decrease fertility in patients of reproductive potential. Menstrual cycle disorders (including amenorrhea), erectile dysfunction, and impotence have been reported. The incidence of hypogonadism may be increased with the use of opioids in high doses or long-acting opioid formulations. It is not known if the effects on fertility are reversible. Monitor patients on long-term therapy (de Vries 2020; Gadelha 2022).

Consider family planning, contraception, and the effects on fertility prior to prescribing opioids for chronic pain to patients who could become pregnant (ACOG 2017; CDC [Dowell 2022]).

Premature ejaculation may contribute to male infertility. Tramadol may be an alternative treatment for premature ejaculation; however, due to the risk of addiction and adverse effects associated with opioid use, it should only be used in patients who have experienced treatment failure with other therapies (AUA/SMSNA [Shindel 2021]; ISSM [Althof 2014]; Martyn-St. James 2015).

Pregnancy Considerations

Tramadol crosses the placenta.

Maternal use of opioids may be associated with poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2022]). Neonatal seizures and fetal death have been reported following maternal use of tramadol. Opioids used as part of obstetric analgesia/anesthesia during labor and delivery may temporarily affect the fetal heart rate (ACOG 2019).

Neonatal abstinence syndrome (NAS)/neonatal opioid withdrawal syndrome (NOWS) may occur following prolonged in utero exposure to opioids (CDC [Dowell 2022]). NAS/NOWS may be life-threatening if not recognized and treated and requires management according to protocols developed by neonatology experts. Presentation of symptoms varies by opioid characteristics (eg, immediate release, sustained release), time of last dose prior to delivery, drug metabolism (maternal, placental, and infant), net placental transfer, as well as other factors (AAP [Hudak 2012]; AAP [Patrick 2020]). Clinical signs characteristic of withdrawal following in utero opioid exposure include excessive crying or easily irritable, fragmented sleep (<2 to 3 hours after feeding), tremors, increased muscle tone, or GI dysfunction (hyperphagia, poor feeding, feeding intolerance, watery or loose stools) (Jilani 2022). NAS/NOWS occurs following chronic opioid exposure and would not be expected following the use of opioids at delivery (AAP [Patrick 2020]).

Monitor infants of mothers on long-term/chronic opioid therapy for symptoms of withdrawal. Symptom onset reflects the half-life of the opioid used. Monitor infants for at least 3 days following exposure to immediate-release opioids; monitor for at least 4 to 7 days following exposure to sustained-release opioids (AAP [Patrick 2020]; CDC [Dowell 2022]). Monitor newborns for excess sedation and respiratory depression when opioids are used during labor.

When opioids are needed to treat acute pain in pregnant patients, the lowest effective dose for only the expected duration of pain should be prescribed (CDC [Dowell 2022]).

Opioid use for pain following vaginal or cesarean delivery should be made as part of a shared decision-making process. A stepwise, multimodal approach to managing postpartum pain is recommended. A low-dose, low-potency, short-acting opioid such as tramadol can be used to treat acute pain associated with delivery when needed (ACOG 2021).

Opioids are not preferred for the treatment of chronic noncancer pain during pregnancy; consider strategies to minimize or avoid opioid use. Advise pregnant patients requiring long-term opioid use of the risk of NAS/NOWS and provide appropriate treatment for the neonate after delivery. NAS/NOWS is an expected and treatable condition following chronic opioid use during pregnancy and should not be the only reason to avoid treating pain with an opioid in pregnant patients (ACOG 2017; CDC [Dowell 2022]). Do not abruptly discontinue opioids during pregnancy; taper prior to discontinuation when appropriate, considering the risks to the pregnant patient and fetus if maternal withdrawal occurs (CDC [Dowell 2022]).

Breastfeeding Considerations

Tramadol and the active M1 metabolite are present in breast milk. M1 has stronger opioid activity than tramadol. Actual exposure to a breastfeeding infant may depend on the mothers CYP2D6 metabolism (Salman 2011).

Due to the potential for serious adverse events in the breastfed infant (including excess sedation and respiratory depression), use during breastfeeding is not recommended by the manufacturer. Nonopioid analgesics are preferred for lactating patients who require pain control peripartum or for surgery outside of the postpartum period. When opioids are needed for lactating patients, use the lowest effective dose for the shortest duration of time to limit adverse events in the mother and breastfeeding infant. However, when an opioid is needed to treat maternal pain, tramadol is not recommended (AAP [Sachs 2013]; ABM [Martin 2018]; ABM [Reece-Stremtan 2017]; WHO 2002).

When chronic opioids are prescribed prenatally and continued postpartum, breastfeeding may be initiated to help mitigate potential newborn withdrawal; monitor both the mother and the infant (AAP [Meek 2022]; AAP [Patrick 2020]).

Monitor infants exposed to opioids via breast milk for drowsiness, sedation, feeding difficulties, or limpness (ACOG 2019). Withdrawal symptoms may occur when maternal use is discontinued, or breastfeeding is stopped.

Monitoring Parameters

Pain relief, respiratory and mental status/alertness (especially in patients on concomitant CNS depressants, including benzodiazepines), blood pressure, heart rate; blood glucose if hypoglycemia is suspected; signs/symptoms of hyponatremia (eg, confusion, disorientation) especially during initiation of therapy; bowel function; signs/symptoms of tolerance, substance use disorder, abuse, misuse, or suicidal ideation; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013); signs and symptoms of serotonin syndrome such as mental status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile BP, hyperthermia), neuromuscular changes (eg, hyperreflexia, incoordination), and/or GI symptoms (eg, nausea, vomiting, diarrhea); signs and symptoms of neonatal withdrawal syndrome in infants born to mothers using opioids during pregnancy (eg. irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight); during discontinuation of therapy monitor pain control, withdrawal symptoms, mood changes, suicidal ideation, and for use of other substances.

Alternate recommendations: Subacute or chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. In patients with subacute pain initially treated for acute pain, reassess pain and function after 30 days to address potentially reversible causes of pain and prevent unintentional long-term opioid therapy. In patients on long-term therapy, re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Toxicology testing is recommended prior to initiation and at least yearly (includes controlled prescription medications, illicit drugs of abuse, and benzodiazepines). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (CDC [Dowell 2022]).

Reference Range

100 to 300 ng/mL; however, serum level monitoring is not required

Mechanism of Action

Tramadol and its active metabolite (M1) binds to μ-opiate receptors in the CNS causing inhibition of ascending pain pathways, altering the perception of and response to pain; also inhibits the reuptake of norepinephrine and serotonin, which are neurotransmitters involved in the descending inhibitory pain pathway responsible for pain relief (Grond 2004)

Pharmacokinetics (Adult Data Unless Noted)

Onset of action: Immediate release: Within 1 hour; Peak effect: 2 to 3 hours

Distribution: Vd: IV: 2.6 L/kg (males); 2.9 L/kg (females)

Protein binding, plasma: ~20%

Metabolism: Extensively hepatic via demethylation (mediated by CYP3A4 and CYP2D6), glucuronidation, and sulfation; has pharmacologically active metabolite formed by CYP2D6 (M1; O-desmethyl tramadol)

Bioavailability:

Immediate release: ~75%

Extended release: ~85% to 95% (as compared to immediate release)

Half-life elimination:

Immediate release: 6.3 ± 1.4 hours; active metabolite (M1): 7.4 ± 1.4 hours; prolonged in elderly

Extended-release:

Capsules: ~10 hours; active metabolite (M1): ~11 hours

Tablets: ~7.9 hours; active metabolite (M1): 8.8 hours.

Time to peak, plasma:

Immediate release: ~2 hours; active metabolite (M1): 3 hours

Extended release: ~4 to 12 hours; active metabolite (M1): ~5 to 15 hours

Excretion: Urine (~30% as unchanged drug; 60% as metabolites)

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Altered kidney function: Decreased rate and extent of excretion.

Hepatic function impairment:

Immediate release: Metabolism is reduced in advanced cirrhosis, resulting in increased AUC and increased elimination half-life (13 hours [tramadol], 19 hours [M1]).

Extended release: Exposure is decreased ~50% with increased severity of hepatic impairment.

Older adult: Maximum serum concentration is increased and elimination half-life prolonged.

Sex:

Immediate release: Women had a 12% higher peak tramadol concentration and a 35% higher area under the curve (AUC) compared to men.

Extended release: AUC were somewhat higher in females than in males.

Note: Concentrations of tramadol were ~20% higher in “poor metabolizers” versus “extensive metabolizers,” while M1 concentrations were 40% lower.

Brand Names: International
International Brand Names by Country
For country code abbreviations (show table)

  • (AE) United Arab Emirates: Tramal | Tramundin;
  • (AR) Argentina: Adamon | Ana Q | Calmador | Calmador cb | Cloq | Fada tramadol | Lafedol | Lixidol | Nobligan | Supragesic t nf | Trama klosidol | Tramacat | Tramadol biotenk | Tramadol denver farma | Tramadol kilab | Tramadol pharmavial | Tramadolten | Tramal | Tramanovag | Tramaxedenol | Tramustin | Ultracalmans | Ultragesic | Ultragesic cb;
  • (AT) Austria: Adamon | Contramal | Cromatodol | Noax uno | Nobligan | Nycodol | Tradolan | Tramabene | Tramadol Hydrochloride Actavis | Tramadol-1a pharma gmbh | Tramadolor | Tramal | Tramastad | Tramundal;
  • (AU) Australia: Apo Tramadol | Chemmart tramadol | Cm tramadol | Durotram | Ga Tramadol | Lodam | Tramadol | Tramadol actavis | Tramadol an | Tramadol generichealth | Tramadol sandoz | Tramadol scp | Tramahexal | Tramal | Tramedo | Tw tramadol | Zydol;
  • (BD) Bangladesh: Anadol | Dolonil | Doloran | Dolorex | Dolotram | Imadol | Kingdol | Lucidol | Opalgic | Pendol | Rapidol | Syndol | Tendia | Tramacap | Tramadol | Tramal | Tramanil | Tranal | Trd contin | Trol | Trumen | Utramal | Utramal retard | Winpain | Xtrapel | Zydol;
  • (BE) Belgium: Contramal | Doctramado | Dolzam | Dolzam uno | Tradonal | Tramadol bexal | Tramadol EG | Tramadol eurogenerics | Tramadol krka | Tramadol mylan | Tramadol sandoz | Tramadol teva generics belgium | Tramium;
  • (BF) Burkina Faso: Dolora | Joridol | T dol | T-dol sr | Tramagen | Trambax;
  • (BG) Bulgaria: Mabron | Mabron mr | Slovadol | Tramadol | Tramadol lannacher | Tramal | Tramalgin;
  • (BR) Brazil: Anangor | Cloridrato de tramadol | Dorless | Gesico | Gesico retard | Keltix | Megadol | Novotram | Rapitram | Sensitram | Sinedol | Sylador | Timasen | Timasen sr | Trabilin | Tramaden | Tramadon | Tramal | Tramal retard | Tramaliv | Traum retard | Trol | Unidol | Zamadol;
  • (CH) Switzerland: Ecodolor | Tradonal | Tramactil Uno | Tramadol helvepharm | Tramadol Mepha | Tramadol retard zentiva | Tramadol sandoz | Tramadol Streuli | Tramadol zentiva | Tramal | Tramundin;
  • (CI) Côte d'Ivoire: Diadol | Dolex | Dolora | Dolora id | Domadol | Joridol | Lodamar | Mepol | Nomadol | Plazadol | Radol | T dol | T-dol sr | Talodol | Tradolan | Tramacip | Tramaclass | Tramadis | Tramadol denk | Tramagen | Tramas | Trambax | Tramfiz | Zamudol lp | Zitram sr;
  • (CL) Chile: Adolonta | Eufindol lp | Nobligan | Timarol | Tramal | Tramal Ir | Zaledor | Zodol;
  • (CN) China: Bei ping | Hua qu | Lang fu qing | Mabron | Qi mai te | Qi man ding | Qi zhi | Qu teng | Qu tong kang | Tai de luo | Ti ma er | Tramadol | Tramadol hydrochloride sustained release tablets (ii) | Tramadol hydrochloride sustained release tablets (iii) | Tramal | Tramcontin | Xiang yang | Ying xin kang | Yu tong;
  • (CO) Colombia: Carmucol | Sintral | Tradol | Tramacontin | Tramadol | Tramadol clorhidrato | Tramadol ecar | Tramadol mk | Tramal | Tramal long | Tramasindol | Tramydol | Wintradol;
  • (CZ) Czech Republic: Mabron | Noax uno | Protradon | Tralgit | Tramabene | Tramadol | Tramadol actavis | Tramadol aurovitas | Tramadol hf | Tramadol kalceks | Tramadol krka | Tramadol mylan | Tramadol sandoz | Tramadol Vitabalans | Tramal | Tramundin;
  • (DE) Germany: Amadol | Jutadol | Nobligan | T long | Tial | Trama | Trama biochemie | Trama dorsch | Trama kd | Trama sanorania | Tramabeta | Tramadoc | Tramadol | Tramadol al | Tramadol aristo | Tramadol Axcount | Tramadol basics | Tramadol Biomo | Tramadol ct | Tramadol denk | Tramadol Dolgit | Tramadol Gruenenthal | Tramadol librapharm | Tramadol mylan | Tramadol Q | Tramadol ratiopharm | Tramadol sandoz | Tramadol stada | Tramadol Temmler | Tramadolor | Tramadura | Tramagetic | Tramagit | Tramal | Tramamerck | Tramawieb | Tramundin | Tramundin retard | Travex one;
  • (DK) Denmark: Dolol | Mandolgin | Mandolgin uno | Tramadol alpharma | Tramadol hexal;
  • (DO) Dominican Republic: Adamon | Dolga | Dolopront | Dotral | Etigesic | Tradolam | Tradolam sr | Tradoxil | Tramadol | Tramadol lam | Tramafran | Tramal;
  • (EC) Ecuador: Budol | Litram | Naxodol | Nobligan | Ramgic | Tradoxil | Tramadol | Tramadol clorhidrato | Tramadol Genfar | Tramadon | Tramal | Tramal long | Tramedif | Zodol;
  • (EE) Estonia: Dolol | Mabron | Olteron | Tramadol | Tramadol stada | Tramadol Vitabalans | Tramadolor | Tramagit | Tramal | Tramundin;
  • (EG) Egypt: Amadol | Contramal | Octotramadol | Rivadol | Trama | Tramadol | Tramal | Tramax | Tramundin | Ultradol;
  • (ES) Spain: Adolonta | Ceparidin | Dolodol | Dolpar | Gelotradol | Tioner | Tralgiol | Tramadol almus | Tramadol apotex | Tramadol aristo | Tramadol aurovitas | Tramadol bayvit | Tramadol bexal | Tramadol cinfa | Tramadol Diasa | Tramadol edigen | Tramadol farmasierra | Tramadol kern | Tramadol krka | Tramadol mabo | Tramadol mylan | Tramadol normon | Tramadol ratiopharm | Tramadol retard | Tramadol stada | Tramadol tarbis | Tramadol teva | Tramadol Vegal | Zytram;
  • (ET) Ethiopia: Domadol | E dol | Ramgic | Riseol | Rofy | Rofy retard | Trama | Tramadex | Tramadol | Tramadol kalceks | Tramal denk | Tramasure | Verdol | Zimadol;
  • (FI) Finland: Dolatramyl | Tradolan | Tramadin | Tramadol generics | Tramadol hexal | Tramadol krka | Tramadol sandoz | Tramadol Vitabalans | Tramagetic | Tramal | Trambo | Tramium;
  • (FR) France: Contramal | Monocrixo | Monotramal | Topalgic | Tramadol | Tramadol actavis | Tramadol almus | Tramadol arrow | Tramadol biogaran | Tramadol cristers | Tramadol evolugen | Tramadol evolugen L.P. | Tramadol g gam | Tramadol gnr | Tramadol hcs | Tramadol ivax | Tramadol krka lp | Tramadol merck | Tramadol mylan | Tramadol mylan generiques lp | Tramadol qualimed | Tramadol Ranbaxy | Tramadol ratiopharm | Tramadol sandoz | Tramadol teva | Tramadol winthrop | Tramadol zydus | Tramadol Zydus L. P. | Trasedal | Zamudol;
  • (GB) United Kingdom: Brimisol pr | Dromadol | Mabron | Maneo | Marol | Maxitram | Nobligan | Tradorec xl | Tramadol | Tramadol almus | Tramadol arrow | Tramadol cox | Tramadol kent | Tramadole | Tramake | Zamadol | Zeridame | Zydol | Zytram SR;
  • (GH) Ghana: Entradol;
  • (GR) Greece: Oxxalgan | Tramal | Tramal sr | Tropium | Vibralis;
  • (HK) Hong Kong: Acugesic | Koridol | Locidol | Lucidol | Mabron | Paindol | Sefmal | Tamadol | Trabilin 100 | Tradolgesic | Tradonal | Tramada | Tramadol | Tramadol hameln | Tramal | Tramo | Trasic;
  • (HR) Croatia: Lumidol | Toram | Tramacur | Tramadol | Tramadol Farmal | Tramadol Farmal retard | Tramadolor | Tramal | Tramundin retard;
  • (HU) Hungary: Adamon | Contramal | Ralgen | Tramadol | Tramadol actavis | Tramadol al | Tramadol kalceks | Tramadol ratiopharm | Tramadol Vitabalans | Tramadol-k | Tramadolor | Tramalgic;
  • (ID) Indonesia: Andalpha | Bellatram | Bestram | Centrasic | Contram | Corsadol | Dolana | Dolgesik | Dolika | Dolocap | Dolsic | Domedon | Forgesic | Intradol | Kamadol | Katrasic | Nufapotram | Orasic | Pinorec | Radol | Seminac | Simatral | Tradomed | Tradonal | Tradosik | Tradyl | Tragesik | Tramadol | Tramal | Tramofal | Trasik | Traumasik | Trunal | Tugesal | Zephanal | Zumatram;
  • (IE) Ireland: Biodol | Bymadol | Tradol | Tradol sr | Tramadol | Tramadol krka | Tramake | Tramapine | Xymel | Zydol;
  • (IL) Israel: Trabar | Tramadex | Tramal;
  • (IN) India: Adamon | Admadol | Altranova | Anazac | Bestodol | Biotram | Cemadol | Contramal | Dolmark | Dolmundin | Dolodol | Dolofort | Dolomed t | Dolotram | Dolstar | Dolus | Domadol | Gufidol | Hextradol | Kamadol | Lomadol | Lydol | Neutram | Nexdol | Nobligan | Opi Ot | Orchidol | Painadol | Pentazen | Postadol | Prado | Ramax | Ramcet | Relidol | Sayodol | Sedate | Stemadol | Stradol | Strom | Supridol | Takol | Tdx | Tol | Topdol | Traceta | Tram Proxyvon | Tramacip | Tramacon | Tramacon sr | Tramad | Tramadex | Tramadin | Tramadol | Tramaflam | Tramagesic | Tramapen | Tramaphar | Tramasol | Tramasure | Tramatas | Tramax | Tramazac | Tramazac-TC | Tramaze | Tramazide | Trambax | Tramcel | Tramed | Tramol | Tramore | Tramot | Trandol | Transic | Tranzat | Tranzex | Trapsure | Trasic | Trax | Trazac | Trd conject | Trd contin | Troma | Tromanil | Trump | Tyridol | Ultramed | Unidol | Urgendol | Vicadol | Victadol | Zamadol | Zyrotram;
  • (IS) Iceland: Tramol L;
  • (IT) Italy: Adamon | Contramal | Fortradol | Fraxidol | Prontalgin | Tradonal | Traflash | Tralodie | Traloide | Tramadolo | Tramadolo age | Tramadolo hex | Tramadolo krka | Tramadolo Ranbaxy | Tramadolo viatris | Tramalin | Tramamed | Unitrama;
  • (JO) Jordan: Analdol | Mabron | Nomal | Painol | Tarol | Tradox | Tramadon | Tramal;
  • (JP) Japan: Onetram | Tramal | Tramal kowa | Twotram;
  • (KE) Kenya: Amadol | Amadol sr | Anadol | Asdol | Cipadol | Coltra | Dolafree sr | Dolonil | Doltam | Domadol | E dol | Essmadol | Kridol | Metadol | Penoff | Plazadol | Ramgic | Sacmol | Strom | Strom sr | Takol cr | Tenadol | Trabilin | Tradmin | Trama | Tramacip | Tramadex | Tramadol | Tramadol denk retard | Tramadol hameln | Tramafred | Tramal | Tramal sr | Tramamark | Tramamed | Tramaspas | Tramasure | Tramavent | Tramaz | Tramazac | Tramgesic Flashtabs | Tramsun | Trasic | Trd contin | Unitram | Upmadol | Urgendol | Urgendol sr | Utram | Zimadol;
  • (KR) Korea, Republic of: Ausmadol | Campex | Compa | Dolma | Dongkoo tramadol hcl | Exopen | Gl tramadol hcl | Hanall tramadol | Humedix tramadol | Initramadol | K madol | Kontram xl | Madol | Maritrol | Neomadol | Newdolpine | Newtram | O.p-pain | Peintra | Penimadol | Potendol | Ramado | Ramadol | Ratrol | Sinil trimadol | Tamadol | Tandol | Timarol | Toranzin | Tra | Tracompa | Tradol | Tradom | Tramaconti | Tramadol | Tramadol HCL | Tramadol hcl huons | Tranol | Tratol | Tridol | Tridol retard | Trimadol | Trodon | Trol | White trama | Woolpain | Zipan | Zyrtam xl | Zytram cr | Zytram XL;
  • (KW) Kuwait: Nomal | Tramadol | Tramal | Tramundin;
  • (LB) Lebanon: Mabron | Tramal | Tramal retard | Tramarivo | Tramundin retard;
  • (LT) Lithuania: Mabron | Mabron retard | Protradon | Tramadol | Tramadol kalceks | Tramadol Vitabalans | Tramadolor | Tramal | Tramazac;
  • (LU) Luxembourg: Contramal | Doctramado | Dolzam | Tradonal | Tramadol EG | Tramal | Tramium | Traretmylan;
  • (LV) Latvia: Adamon | Dolol | Mabron | Trabar | Tramadol | Tramadol kalceks | Tramadol Vitabalans | Tramadolor | Tramadolum | Tramal | Tramal stada | Tramalgin | Tramundin;
  • (MA) Morocco: Nomadol | Tramadol | Tramadol normon | Tramal | Tramium | Tremadol | Triadol;
  • (MX) Mexico: Adiolol | Afortixa | Citra | Dalerest | Desigort | Dolisev | Dolne | Dolne c | Durodor | Gencatrol | Gencatrol rtd | Jasfer | Nobligan | Noxvatel | Pisazol | Prontofort | Relivium | Tandeaur | Tradol | Tradol retard | Tragesic | Tralic | Tramadol | Tramed | Tramundin | Trexol | Veldrol;
  • (MY) Malaysia: Acugesic | Anadol | Analab | Domadol | Hp tramadol sr | Mabron | Mabron retard | Pengesic | Sefmal | Trabilin | Tracidol | Tramada | Tramadol | Tramadolor | Tramal | Tramazac | Tramium | Tramox;
  • (NG) Nigeria: Ac tramadol | Bg tragesic | Domadol | Felitone tramadol | Genmadol | Nci tramadol | New divine tramadol | Rebok tramadol | Rgi tramadol | Spectradol | Tra n | Trabilin | Tradyl | Tramadol | Tramadol marcolivia | Tramal | Tramed | Trampain | Tramyoung | Urgendol | Zotrama;
  • (NL) Netherlands: Tramadol | Tramadol HCL | Tramadol hcl A | Tramadol hcl Alpharma | Tramadol HCl Aurobindo | Tramadol HCl CF | Tramadol Hcl Merck | Tramadol HCl PCH | Tramadol hcl prolepha | Tramadol hcl Sandoz | Tramagetic | Tramal | Tramal-z;
  • (NO) Norway: Dolatramyl | Nobligan | Tradolan | Tramadol | Tramadol actavis | Tramadol gea | Tramadol hexal | Tramadol panpharma | Tramadol ratiopharm | Tramadol Vitabalans | Tramagetic | Tramagetic OD | Tramagetic retard | Tramal | Tramal long | Zytram bid | Zytram XL;
  • (NZ) New Zealand: Arrow Tramadol | Tramadol | Tramal | Zytram BD;
  • (PE) Peru: Cesalgin | Dolex | Recalm | Tradolor | Tram | Tramacor | Tramadol | Tramadol clorhidrato | Tramadolip | Tramadoliphar | Tramafer | Tramal | Tramedif | Zodol;
  • (PH) Philippines: Algotrol | Ambidol | Biopyrex 01 | Diaram | Dolmal | Dolotral | Dolpain | Dolpaz | Dolright | Dynatram | E dol | Gesidol | Gesitram | Mardol | Microdol | Milador | Mns | Mosepan | Newdorphin | Pengesic | Penimadol | Radol | Relidol | Ridil | Rounox | Saphtram | Siverol | Tdl | Tolma | Tracaine | Tradomal | Tradonal | Tramadex | Tramadin | Tramadol | Tramadol Pacific | Tramal | Tramalin | Tramazac | Tramaze | Tramide | Tramkor | Tramosic | Tramundin | Tramundin ir | Trump | Unitral | Vheradol | Vidadol | Vitral | Zitram sr;
  • (PK) Pakistan: Acugesic | Adetol | Adolan | Allay | Allay sr | Antram plus | Baritral | Calfina | Calfina cr | Campex | Codogesic sr | Conzi | Damor | Gesidol | Hidol | Irzadol | Lamadol | Madol | Magadol | Maradol | Merlon | Mictra | Misadol | Newtra | Nopa | Omnidol | Opigesic | Palmadol | Pantra | Penimadol | Pomperc | Postadol | Rama D | Ramadol | Ramatram | Relidol | Scibid | Sologesic | Sologesic sr | Symol | T dol | Tamadol | Tamlov | Taram | Taram sr | Taxidol sr | Tazdol | Tomdol | Tonoflex | Tradol | Tradolint | Trafast | Tramacure | Tramadan | Tramadol | Tramagesic | Tramajet | Tramal | Tramal 100 | Tramal sr | Tramarooq | Tramaway | Tramax | Tramed | Tramfold | Tramofix | Tramozet | Trascot | Trascot er | Traumanil | Trazone | Tred | Tremendovs | Tromid sr | Trompol | Trumed | Trunal dx | Tymil | Ultrame | Vexnil | Volpan | Volpan sr | Votadol | Zultra | Zultra sr | Zumatram;
  • (PL) Poland: Adamon | Amadol | Noax | Oratram | Poltram | Poltram retard | Slovadol | Tramadol | Tramadol 1 A Pharma | Tramadol aurovitas | Tramadol kalceks | Tramadol krka | Tramadol lannacher | Tramadol Vitabalans | Tramahexal | Tramal | Tramal retard | Tramundin | Trodon;
  • (PR) Puerto Rico: Conzip | Ryzolt | Tramadol | Tramadol HCL | Tramadol hcl ER | Tramadol hydrochloride extended release | Ultram;
  • (PT) Portugal: Gelotralib | Nobligan | Paxilfar | Tram u ron od | Tramadol | Tramadol actavis | Tramadol andromaco | Tramadol Azevedos | Tramadol basi | Tramadol generis | Tramadol krka | Tramadol meda | Tramadol mylan | Tramal | Travex | Tridural;
  • (PY) Paraguay: Cesalgin | Fisioflex | Thalfendrol | Trama klosidol | Tramadol caplin point | Tramadol dallas | Tramadol interlabo | Tramadol long | Tramadol prosalud | Tramadol sanderson | Tramal | Zodol;
  • (QA) Qatar: Invodol | Mabron | Mabron MR | Marol | Nomal | Trabar-100 | Tramal | Tramal Retard | Tramedo SR | Tramulief SR | Zydol;
  • (RO) Romania: K alma | Mabron | Tramadol | Tramadol al | Tramadol kalceks | Urgendol;
  • (RU) Russian Federation: Mabron | Plazadol | Sintradon | Tradol | Tramadol | Tramadol Akri | Tramadol Aveksima | Tramadol avexima | Tramadol gr | Tramadol kalcex | Tramadol m | Tramadol nycomed | Tramadol Plethico | Tramadol ratiopharm | Tramadol retard | Tramagit | Tramaklosidol | Tramal | Tramalgin | Tramolin;
  • (SA) Saudi Arabia: Mabron | Nomal | Trabilin | Tramadol | Tramal;
  • (SE) Sweden: Dolatramyl | Dolol | Gemadol | Nobligan | Tiparol | Tradolan | Tramadol 2care4 | Tramadol actavis | Tramadol alternova | Tramadol astrazeneca | Tramadol Aurobindo | Tramadol hexal | Tramadol krka | Tramadol meda | Tramadol medartuum | Tramadol mylan | Tramadol ratiopharm | Tramadol retard krka | Tramadol retard medartuum | Tramadol scand pharma | Tramadol searle | Tramadol stada | Tramadol Vitabalans | Tramuno;
  • (SG) Singapore: Acugesic | Mabron | Pengesic | Sefmal | Tracidol | Tramadol | Tramal;
  • (SI) Slovenia: Tadol | Tramadol Vitabalans | Tramal | Tramundin;
  • (SK) Slovakia: Adamon | Mabron | Noax uno | Protradon | Tralgit | Tramabene | Tramadol | Tramadol actavis | Tramadol al | Tramadol mylan | Tramadol sandoz | Tramadol Vitabalans | Tramal;
  • (TH) Thailand: Amanda | Ammitram | Analab | Crismal | Famadol | Gatadol | J.V.Dol | Mabron | Madol | Madola | Mardol | Matradol | Millidol | Modsenal | Paindol | Pharmadol | Ramadol | Sefmal | Sonamol | Tadol | Tamolan | Tasidol | Tindol | Tracine | Tradolgesic | Tradonal | Tragesic | Tramacap | Tramache | Tramada | Tramadil | Tramadol | Tramadol nida | Tramadol ratiopharm | Tramadol stada | Tramadol T P | Tramadon | Tramal | Tramamed | Tramax | Tramazac | Tramoda | Tramomet | Trapidol | Trasic | Traumed | Troc | Trosic | Vesnon V | Volcidol | Volcidol-s;
  • (TN) Tunisia: Astradol | Latifex | Souladol | Tramadis | Tramal;
  • (TR) Turkey: Contramal | Madol | Ramadex | Tradolex | Tramadolor | Tramosel | Ultramex;
  • (TW) Taiwan: Camadol | Limadol | Muaction | Painlax | Ramgic | Tadol | Tradol | Tramadol | Tramadol sandoz | Tramal | Tramazac | Tramed | Tramtor;
  • (TZ) Tanzania, United Republic of: Amadol;
  • (UA) Ukraine: Contramal | Tradol | Tramadol | Tramadol b | Tramadol kalceks | Tramadol m | Tramagit | Tramal | Tramalgin | Tramol;
  • (UG) Uganda: Agotram | Amadol | Asdol | Domadol | E dol | Mabron | Nemadol | Pengesic sr | Ramgic | Strom | Supridol | T dol | Trabilin | Tradmin | Tram dol | Tramaren | Tramazac | Trd contin | Urgendol;
  • (UY) Uruguay: Calmol | Cesalgin | Dalgion | Nobligan | Profundol | Tramadol;
  • (VE) Venezuela, Bolivarian Republic of: Tradol | Tramadol | Tramadol clorhidrato | Tramal | Tramal long;
  • (VN) Viet Nam: Osmadol | Tramabad | Trasolu;
  • (ZA) South Africa: Austell tramadol | Dolotram | Doltrex | Domadol | Nobligan | Tramahexal | Tramal | Tramaspen | Tramazac | Zytram;
  • (ZM) Zambia: Dolo doc | Domadol | Takol cr | Tamadol | Trama | Tramadol denk | Tramahexal | Tramazac | Zitram sr;
  • (ZW) Zimbabwe: Domadol | Tramadol | Tramica
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