Version July 2025
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.
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.
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.
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 of even one dose of tramadol, especially by children, can result in a fatal overdose of tramadol.
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.
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.
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.
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.
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 (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.
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.
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.
(For additional information see "Tramadol: Drug information")
Dosage guidance:
Safety: Consider prescribing naloxone or nalmefene 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:
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 prefer other opioids due to wide interpatient variability in tramadol metabolism, related 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 or nalmefene. 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 (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.
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 (Ref):
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.
The liver dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Matt Harris, PharmD, MHS, BCPS, FAST, FCCP; 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 liver impairment, tramadol is subject to reduced hepatic metabolism, which may result in ineffective pain control (Ref). Dose recommendations for liver 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 liver impairment (Ref).
Liver impairment prior to treatment initiation:
Initial or dose adjustment in patients with preexisting liver cirrhosis :
Pain management: Moderate to severe:
Acute pain:
Child-Turcotte-Pugh class A: Immediate release: 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: Immediate release: Oral: Initial: 25 mg every 8 to 12 hours as needed; may increase to a maximum of 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).
Liver impairment developing in patient already receiving tramadol:
Chronic disease progression (eg, outpatient ):
Pain management: Moderate to severe:
Baseline to 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; 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).
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 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 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
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)
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)
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)
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)
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%)
|
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
|
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 |
|
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 |
|
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 (Ref), toxic epidermal necrolysis (Ref), 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 (Ref), serotonin syndrome (Ref), 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 (Ref)
Endocrine & metabolic: Adrenocortical insufficiency (Ref), hypoglycemia (within 30 days of initiation (Ref); 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%) (Ref)
Nervous system: Allodynia (opioid-induced hyperalgesia) (Ref), delirium (Ref)
Neuromuscular & skeletal: Femoral neck fracture (Ref)
Ophthalmic: Cataract, mydriasis (Ref)
Otic: Deafness
Respiratory: Pulmonary edema, respiratory depression (Ref)
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.
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.
• 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 or nalmefene 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/nalmefene access: Discuss the availability of naloxone or nalmefene 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 or nalmefene 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 or nalmefene (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 or nalmefene, 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.
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).
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.
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, 200 mg, 300 mg
Solution, Oral, as hydrochloride:
Qdolo: 5 mg/mL (473 mL [DSC]) [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, 75 mg, 100 mg
Tablet Extended Release 24 Hour, Oral, as hydrochloride:
Generic: 100 mg, 200 mg, 300 mg
Yes
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 (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
75 mg (per each): $5.72
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.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
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:
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
5 mg/mL Oral Suspension
A 5 mg/mL oral suspension may be made with tablets and either Ora-Sweet SF or a mixture of 30 mL Ora-Plus and 30 mL strawberry syrup. Crush six 50 mg tramadol tablets in a mortar and reduce to a fine powder. Add small portions of the chosen vehicle and mix to a uniform paste; mix while adding vehicle in incremental proportions to almost 60 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 60 mL. Label "shake well before use." Stable for 90 days refrigerated or at room temperature.
C-IV
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).
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.
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
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
Immediate-release formulations (tablet, oral solution): Management of pain severe enough to require opioid analgesic and in which alternative treatments are inadequate (FDA approved in adults).
Extended-release formulations:
Capsule: Management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and in which alternative treatment options are inadequate (FDA approved in adults).
Tablet: Management of severe and persistent pain for an extended period of time with an opioid analgesic in which alternative treatment options are inadequate (FDA approved in adults).
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
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).
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]).
Tramadol is identified in the Screening Tool of Older Person's Prescriptions (STOPP) criteria as a potentially inappropriate medication in older adults (≥65 years of age) due to an increased risk of exacerbation of constipation. Opioids are not recommended as first-line treatment of mild pain or long-term treatment of osteoarthritis. Short-acting opioids should be available for breakthrough pain in patients on long-acting opioids. Avoid use in patients with a history of recurrent falls (O’Mahony 2023).
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]).
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]
Substrate of CYP2B6 (Minor), CYP2D6 (Major), CYP3A4 (Major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential;
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.
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
Agents with Clinically Relevant Anticholinergic Effects: May increase adverse/toxic effects of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor
Ajmaline: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Almotriptan: May increase serotonergic effects 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
Alvimopan: Opioid Agonists may increase adverse/toxic effects 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 increase neuroexcitatory and/or seizure-potentiating effects of Amifampridine. Risk C: Monitor
Amisulpride (Oral): Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Amisulpride (Oral). Specifically, the risk of seizures may be increased. Risk C: Monitor
Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Amphetamines: May increase analgesic effects of Opioid Agonists. Risk C: Monitor
Amphetamines: May increase serotonergic effects 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
Androgens: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor
Antidiabetic Agents: May increase hypoglycemic effects of Hypoglycemia-Associated Agents. Risk C: Monitor
Antiemetics (5HT3 Antagonists): May increase serotonergic effects 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
Antipsychotic Agents: Serotonergic Agents (High Risk) may increase adverse/toxic effects of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor
ARIPiprazole Lauroxil: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ARIPiprazole Lauroxil. Specifically, the risk of seizures may be increased. Risk C: Monitor
ARIPiprazole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of ARIPiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor
Artemether and Lumefantrine: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor
Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Benperidol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Benperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor
Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Blonanserin: CNS Depressants may increase CNS depressant effects 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
Brexpiprazole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Brexpiprazole. Specifically, the risk of seizures may be increased. Risk C: Monitor
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromopride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Buprenorphine: CNS Depressants may increase CNS depressant effects of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider Therapy Modification
Buprenorphine: May decrease therapeutic effects of Opioid Agonists. Management: Seek alternatives to buprenorphine in patients receiving pure opioid agonists. If combined in certain pain management situations (eg, surgery), monitor for symptoms of therapeutic failure/high dose requirements or opioid withdrawal symptoms. Risk D: Consider Therapy Modification
BuPROPion: May increase neuroexcitatory and/or seizure-potentiating effects of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor
BusPIRone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
BusPIRone: May increase serotonergic effects 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
Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor
CarBAMazepine: TraMADol may decrease therapeutic effects of CarBAMazepine. TraMADol may increase CNS depressant effects of CarBAMazepine. CarBAMazepine may decrease serum concentration of TraMADol. Risk X: Avoid
Cariprazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Cariprazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification
Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification
Chlormethiazole: May increase CNS depressant effects 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 increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Clofazimine: May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor
CNS Depressants: May increase CNS depressant effects 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 increase serum concentration of TraMADol. CYP2D6 Inhibitors (Moderate) may decrease active metabolite exposure of TraMADol. Risk C: Monitor
CYP2D6 Inhibitors (Strong): May increase serum concentration of TraMADol. CYP2D6 Inhibitors (Strong) may decrease active metabolite exposure of TraMADol. Risk C: Monitor
CYP3A4 Inducers (Moderate): May decrease serum concentration of TraMADol. Risk C: Monitor
CYP3A4 Inducers (Strong): May decrease serum concentration of TraMADol. Risk C: Monitor
CYP3A4 Inhibitors (Moderate): May increase serum concentration of TraMADol. CYP3A4 Inhibitors (Moderate) may increase active metabolite exposure of TraMADol. Risk C: Monitor
CYP3A4 Inhibitors (Strong): May increase serum concentration of TraMADol. CYP3A4 Inhibitors (Strong) may increase active metabolite exposure of TraMADol. Risk C: Monitor
Dapoxetine: May increase serotonergic effects 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
Daridorexant: May increase CNS depressant effects 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 increase hyponatremic effects of Desmopressin. Risk C: Monitor
DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects 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 increase serotonergic effects 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
Dextromethorphan: May increase serotonergic effects 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
Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Digoxin: TraMADol may increase serum concentration of Digoxin. Risk C: Monitor
Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor
Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Diuretics: Opioid Agonists may increase adverse/toxic effects of Diuretics. Opioid Agonists may decrease therapeutic effects of Diuretics. Risk C: Monitor
DroPERidol: May increase CNS depressant effects 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 increase adverse/toxic effects of TraMADol. The risk for serotonin syndrome/serotonin toxicity and seizures may be increased with this combination. DULoxetine may decrease therapeutic effects 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
Eletriptan: May increase serotonergic effects 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
Eluxadoline: Opioid Agonists may increase constipating effects of Eluxadoline. Risk X: Avoid
Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor
Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ergot Derivatives: May increase serotonergic effects 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
Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid
Flunitrazepam: CNS Depressants may increase CNS depressant effects 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 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 decrease therapeutic effects of Gastrointestinal Agents (Prokinetic). Risk C: Monitor
Gepirone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor
Grapefruit Juice: May increase serum concentration of TraMADol. Grapefruit Juice may increase active metabolite exposure of TraMADol. Risk C: Monitor
Herbal Products with Glucose Lowering Effects: May increase hypoglycemic effects of Hypoglycemia-Associated Agents. Risk C: Monitor
HydrOXYzine: May increase CNS depressant effects 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 increase hypoglycemic effects of Hypoglycemia-Associated Agents. Risk C: Monitor
Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies): May decrease therapeutic effects of Opioid Agonists. Opioid Agonists may decrease therapeutic effects of Immune Checkpoint Inhibitors (Anti-PD-1, -PD-L1, and -CTLA4 Therapies). Risk C: Monitor
Iobenguane Radiopharmaceutical Products: TraMADol may decrease therapeutic effects 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
Iohexol: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects 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 increase adverse/toxic effects 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 increase adverse/toxic effects 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 increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Lemborexant: May increase CNS depressant effects 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
Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Linezolid: May increase serotonergic effects of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Risk X: Avoid
Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofexidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification
Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Maitake: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor
Mavorixafor: May increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk X: Avoid
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects 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 increase serotonergic effects of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Risk X: Avoid
Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metoclopramide: May increase serotonergic effects 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
MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor
Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Monoamine Oxidase Inhibitors (Antidepressant): May increase adverse/toxic effects of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased.. Risk X: Avoid
Monoamine Oxidase Inhibitors (Type B): Serotonergic Opioids (High Risk) may increase serotonergic effects of Monoamine Oxidase Inhibitors (Type B). This could result in serotonin syndrome. Risk X: Avoid
Moxonidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nalfurafine: Opioid Agonists may increase adverse/toxic effects of Nalfurafine. Opioid Agonists may decrease therapeutic effects of Nalfurafine. Risk C: Monitor
Nalmefene: May decrease therapeutic effects 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 decrease therapeutic effects of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid
Nefazodone: May increase adverse/toxic effects of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Nefazodone may increase 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
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Ondansetron: May decrease therapeutic effects of TraMADol. Ondansetron may increase serotonergic effects of TraMADol. 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) and diminished tramadol efficacy when these agents are combined. Risk C: Monitor
Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opioid Agonists: CNS Depressants may increase CNS depressant effects 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
Opioids (Mixed Agonist / Antagonist): May decrease analgesic effects 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
Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opipramol: May increase serotonergic effects 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
Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid
Oxitriptan: Serotonergic Agents (High Risk) may increase serotonergic effects 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
Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Oxybate Salt Products: CNS Depressants may increase CNS depressant effects 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 increase CNS depressant effects 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
Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid
Peginterferon Alfa-2b: May decrease serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Risk C: Monitor
Pegvisomant: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor
Pegvisomant: Opioid Agonists may decrease therapeutic effects of Pegvisomant. Risk C: Monitor
Periciazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Periciazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Perphenazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Perphenazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
PHENobarbital: May increase CNS depressant effects of TraMADol. PHENobarbital may decrease serum concentration of TraMADol. Management: Avoid use of tramadol and phenobarbital when possible. Monitor for respiratory depression/sedation. Because phenobarbital is also a moderate CYP3A4 inducer, monitor for decreased tramadol efficacy and withdrawal if combined. Risk D: Consider Therapy Modification
Pipamperone: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Pipamperone. Specifically, the risk of seizures may be increased. Risk X: Avoid
Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor
Polyethylene Glycol-Electrolyte Solution: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Risk C: Monitor
Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor
Primidone: May increase CNS depressant effects of TraMADol. Primidone may decrease serum concentration of TraMADol. Management: Avoid use of tramadol and primidone when possible. Monitor for respiratory depression/sedation. Because primidone is also a moderate CYP3A4 inducer, monitor for decreased tramadol efficacy and withdrawal if combined. Risk D: Consider Therapy Modification
Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Promazine: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Promazine. Specifically, the risk of seizures may be increased. Risk C: Monitor
Prothionamide: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor
Quinolones: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Quinolones may decrease therapeutic effects 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
Ramosetron: Opioid Agonists may increase constipating effects of Ramosetron. Risk C: Monitor
Rilmenidine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects 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 increase sedative effects of ROPINIRole. Risk C: Monitor
Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor
Salicylates: May increase hypoglycemic effects of Agents with Blood Glucose Lowering Effects. Risk C: Monitor
Samidorphan: May decrease therapeutic effects of Opioid Agonists. Risk X: Avoid
Selective Serotonin Reuptake Inhibitor: TraMADol may increase adverse/toxic effects of Selective Serotonin Reuptake Inhibitor. 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
Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): May increase adverse/toxic effects of TraMADol. Specifically, the risk for serotonin syndrome/serotonin toxicity and seizures may be increased. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may decrease therapeutic effects 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
Serotonergic Agents (High Risk, Miscellaneous): Serotonergic Opioids (High Risk) may increase serotonergic effects 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
Serotonergic Non-Opioid CNS Depressants: May increase serotonergic effects of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Serotonergic Non-Opioid CNS Depressants may increase CNS depressant effects of Serotonergic Opioids (High Risk). 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 increase serotonergic effects of TraMADol. This could result in serotonin syndrome. Serotonergic Opioids (High Risk) may increase CNS depressant effects of TraMADol. 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 increase serotonergic effects 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
Serotonin/Norepinephrine Reuptake Inhibitor: May increase adverse/toxic effects 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
Sertindole: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sertindole. Specifically, the risk of seizures may be increased. Risk C: Monitor
Sincalide: Drugs that Affect Gallbladder Function may decrease therapeutic effects 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 increase adverse/toxic effects 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
Somatostatin Analogs: Opioid Agonists may decrease analgesic effects of Somatostatin Analogs. Opioid Agonists may increase analgesic effects of Somatostatin Analogs. Risk C: Monitor
St John's Wort: May increase serotonergic effects of TraMADol. This could result in serotonin syndrome. St John's Wort may decrease 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
Succinylcholine: May increase bradycardic effects of Opioid Agonists. Risk C: Monitor
Sulpiride: Agents With Seizure Threshold Lowering Potential may increase adverse/toxic effects of Sulpiride. Specifically, the risk of seizures may be increased. Risk C: Monitor
Suvorexant: CNS Depressants may increase CNS depressant effects 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 increase serotonergic effects 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
Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid
Tilidine: May increase therapeutic effects of Opioid Agonists. Risk X: Avoid
Tricyclic Antidepressants: Serotonergic Opioids (High Risk) may increase serotonergic effects of Tricyclic Antidepressants. This could result in serotonin syndrome. Tricyclic Antidepressants may increase CNS depressant effects of Serotonergic Opioids (High Risk). 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 increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Vitamin K Antagonists: TraMADol may increase anticoagulant effects of Vitamin K Antagonists. Risk C: Monitor
Zolpidem: CNS Depressants may increase CNS depressant effects 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 increase CNS depressant effects 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
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).
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]).
Pain relief, respiratory rate, blood pressure, and pulse; signs of tolerance, oversedation, withdrawal, abuse, or suicidal ideation; kidney and liver function tests.
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)
Onset of action: Immediate release: Within 1 hour; Peak effect: 2 to 3 hours.
Duration (patient dependent; dosing must be individualized): Immediate release: ~4 to 6 hours; extended release: ~24 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).
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.
