Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Texas Vendor Drug Program formulary coverage.
Tramadol has a nationwide classification as a Schedule IV controlled substance as of Aug. 18, 2014. Key factors contributing to this decision include its potential for abuse and dependence, as well as its link to emergency room visits and deaths related to overdoses1.
Tramadol is a centrally acting, opioid-type analgesic that acts as a mu-opioid receptor agonist and a weak inhibitor of serotonin and norepinephrine reuptake. The immediate-release (IR) formulation is FDA-approved for use in the management of acute or chronic pain in adults severe enough to require an opioid analgesic and for which alternative treatments are inadequate2-6. Tramadol extended-release (ER) is FDA-approved for use the management of severe and persistent pain that requires daily, around-the-clock, long-term treatment with an opioid analgesic and for which alternative treatment options are inadequate2-4,7-9. The tramadol/celecoxib combination is FDA- approved for the acute management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.2-4,10 The tramadol/acetaminophen combination is FDA-approved for the acute (less than 5 days) management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate2-4,11. Following a titration phase, recommended IR tramadol regimens for pain management include doses of 50 mg to 100 mg administered every 4 to 6 hours as needed2-6. For tramadol ER, the recommended initial dose in tramadol IR-naïve patients is 100 mg once daily, titrated every five days in 100 mg increments until pain relief is achieved. For those patients already managed on tramadol IR, the 24-hour dose should be calculated, and the total daily tramadol ER dose should be rounded down to the closest 100 mg increment2-4,7-9. The recommended dose for tramadol in combination with acetaminophen is 2 tablets every 4 to 6 hours as needed for pain relief2-4,11. Maximum recommended doses for tramadol alone and in combination with acetaminophen are summarized in Tables 1 and 2. Dosages exceeding these recommendations will be reviewed.
| Drug Name | Dosage Forms/Strengths | Maximum Recommended Dose |
|---|---|---|
| tramadol immediate-release (Qdolo) | 5 mg/ml solution | 400 mg/day, in divided doses every 4-6 hours |
| tramadol extended-release (generics) | 50 mg, 100 mg tablets |
|
| tramadol extended-release (generics) | 100 mg, 200 mg, 300 mg tablets; 150 mg capsules | 300 mg/day in single daily doses |
| tramadol biphasic extended-release (ConZip, generics) | 100 mg, 200 mg, 300 mg capsules | 300 mg/day in single daily doses |
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| Drug Name | Dosage Forms/Strengths | Maximum Recommended Dose |
|---|---|---|
| tramadol/celecoxib (Seglentis) | 44 mg/56 mg tablets | 176 mg/224 mg per day (2 tablets every 12 hours) |
| tramadol/acetaminophen (generics) | 37.5 mg/325 mg tablets | 300 mg/2600 mg per day (8 tablets per day), in divided doses every 4-6 hours |
Tramadol dosages exceeding 300 mg per day in elderly patients over 75 years of age are not recommended and will be reviewed. In controlled clinical trials, treatment-limiting adverse events were higher in patients over 75 years of age compared to those less than 65 years of age2-11.
In patients with a creatinine clearance less than 30 mL/min, the recommended dosing interval for tramadol IR is every 12 hours and the maximum recommended tramadol dose is 200 mg per day. In patients with severe hepatic impairment, the recommended tramadol IR dose is 50 mg every 12 hours2-6. Tramadol ER should not be given to patients with a creatinine clearance less than 30 mL/min or those with severe hepatic impairment2-4,7-9. The use of the tramadol/celecoxib combination product is not recommended in patients with severe renal impairment or in patients with moderate and severe hepatic impairment. The pharmacokinetics and tolerability in patients with renal and hepatic impairment have not been studied2-4,10. The tramadol/acetaminophen combination should be dosed as 2 tablets every 12 hours in patients with a creatinine clearance less than 30 mL/min and is not recommended for use in patients with hepatic impairment2-4,11.
Tramadol IR, tramadol ER, and tramadol combination formulations are all contraindicated for children younger than 12 years of age. The safety and efficacy of all formulations in pediatric patients has not been established. All formulations are contraindicated for postoperative management in pediatric patients younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of all formulations 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 unless the benefits outweigh the risks2-11 . Following a titration phase, recommended IR tramadol regimens for pain management include doses of 50 mg to 100 mg administered every 4 to 6 hours as needed to not exceed 400 mg daily2-6.
There is no basis for limiting the duration of tramadol therapy as tramadol is promoted for use in chronic pain (e.g., chronic musculoskeletal pain, cancer pain, osteoarthritis, diabetic neuropathy) as well as acute pain events (e.g., postoperative pain, dental extraction pain)2-4,12,13. However, cases of tramadol abuse and dependence have been reported, especially in patients with a history of substance abuse. Therefore, tramadol should be administered cautiously, if at all, to patients with a history of drug or alcohol abuse and/or dependence2-11.
The tramadol/acetaminophen combination is indicated for use in the short-term management of acute pain and should be limited to five days or less of use2-4,11. Patient profiles containing tramadol/acetaminophen prescriptions exceeding this treatment duration will be reviewed.
Adjunctive administration of multiple tramadol dosage forms may result in significant additive adverse events, including respiratory depression, seizures, and serotonin syndrome. Tramadol/acetaminophen combination products should not be used with other tramadol or acetaminophen containing products. Tramadol/celecoxib combination products should not be used with other tramadol or celecoxib containing products2-11. Combined administration of multiple tramadol dosage forms is not recommended and will be reviewed.
Opioid analgesics may enhance the sedative effects as well as other central effects of tramadol. Therefore, the use of tramadol in conjunction with opioid analgesics is recommended cautiously. If tramadol is used concomitantly with another agent that acts upon the central nervous system, the tramadol dosage should be reduced2-11.
Use of tramadol in conjunction with sedative/hypnotics in patients over 75 years of age will be reviewed as these patients may be more sensitive to the additive effects of this drug combination2-11.
Patient profiles will be assessed to identify those drug regimens which may result in clinically significant drug-drug interactions. Drug-drug interactions considered clinically relevant for tramadol are summarized in Table 4. Only those drug-drug interactions identified as clinical significance severe or those considered life-threatening which have not yet been classified will be reviewed:
| Target Drug | Interacting Drug | Interaction | Recommendation | Clinical Significance Level |
|---|---|---|---|---|
| tramadol | barbiturates | adjunctive use may result in respiratory depression, hypotension, profound sedation and potentially death due to additive CNS depression; potential as well for decreasing tramadol levels as barbiturates induce CYP3A4 and tramadol is CYP3A4 substrate | avoid use, if possible; if combined administration necessary, observe for respiratory depression and loss of tramadol analgesic effects | major (CP) |
| tramadol | carbamazepine (CBZ) | potential for reduced analgesic effect due to CBZ-associated CYP3A4 enzyme induction; potential for additive CNS depressant effects, increased seizure risk with concurrent therapy | reserve concomitant use of tramadol and CBZ for patients in whom alternative treatment options are inadequate | major (CP) |
| tramadol | CYP inducers (e.g., phenytoin, rifampin) | potential for reduced tramadol analgesic efficacy as tramadol metabolized by CYP3A4, CYP2D6 | monitor for reduced analgesic effects; adjust dosages as necessary | moderate (CP) |
| tramadol | CYP2D6 inhibitors (e.g., fluoxetine propafenone, ritonavir) | potential for enhanced tramadol pharmacologic/ adverse effects as tramadol metabolized by CYP2D6 | monitor for enhanced analgesic effects, increased adverse effects (including seizures); adjust dosages as necessary | moderate (CP) |
| tramadol | CYP3A4 inhibitors (e.g., amiodarone, erythromycin, ritonavir) | potential for enhanced tramadol pharmacologic/ adverse effects as tramadol metabolized by CYP3A4 | monitor for enhanced analgesic effects, increased adverse effects (including seizures); adjust dosages as necessary | moderate (CP) |
| tramadol | MAOIs+/MAOI-like compounds (e.g., phenelzine, selegiline, rasagiline, linezolid) | potential for additive effects on serotonin and norepinephrine reuptake inhibition; increased risk for respiratory depression, coma, and serotonin syndrome (e.g., nausea, vomiting, hypertension, hyperthermia, cardiovascular collapse) | concurrent administration or prescribing within 14 days of MAOI discontinuation contraindicated | severe, major (CP) |
| tramadol | neuroleptics (e.g., thioridazine, risperidone) | increased seizure risk (mechanism unknown), and potential for increased CNS, respiratory depression | avoid, if possible, in patients with underlying seizure disorders; otherwise, use cautiously together | major (CP) |
| tramadol | opioid analgesics | increased seizure risk | avoid, if possible, in patients with underlying seizure disorders; otherwise, use cautiously together | major (CP) |
| tramadol | serotonergic drugs (e.g., SSRIs/ SNRIs, milnacipran) | increased risk of respiratory depression, hypotension, sedation, and death | Limit the use of opioid analgesics with tramadol to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, reduce initial dosage and titrate to clinical response | moderate, major (CP) |
| tramadol | TCAs^ (e.g., imipramine, cyclobenzaprine) | increased seizure risk (TCAs lower seizure threshold), increased risk of serotonin syndrome (e.g., nausea/vomiting, hypertension, hyperthermia, cardiovascular collapse) as both compounds inhibit serotonin/norepinephrine reuptake | avoid, if possible, in patients with underlying seizure disorders; otherwise, use cautiously together | major (CP) |
| tramadol | warfarin | rare reports of increased prothrombin time with increased bleeding risk; mechanism unknown | closely monitor for INR changes, bleeding; adjust doses as necessary | moderate (CP) |
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