• Moderate to moderately severe pain (extended-release formulations indicated for patients who require around-the-clock pain management).

Contraindicated in:

• Hypersensitivity
• Cross-sensitivity with opioids may occur
• Significant respiratory depression
• Acute or severe bronchial asthma (in unmonitored setting or in absence of resuscitative equipment)
• Known or suspected GI obstruction (including paralytic ileus)
• Concurrent use of monoamine oxidase (MAO) inhibitors (or use within the past 14 days)
• Patients who are acutely intoxicated with alcohol, sedatives/hypnotics, centrally acting analgesics, opioid analgesics, or psychotropic agents
• Patients who are physically dependent on opioid analgesics (may precipitate withdrawal)
• Ultra-rapid metabolizers of CYP2D6 (↑ risk of respiratory depression and death)
• CCr <30 mL/min or hepatic impairment (extended release)
• Lactation: Lactation
• Pedi: Children <12 yr, children <18 yr following tonsillectomy and/or adenoidectomy, and children 12–18 yr who are postoperative; have obstructive sleep apnea, obesity, severe pulmonary disease, or neuromuscular disease; or are taking other medications that cause respiratory depression (↑ risk of respiratory depression and death).

Use Cautiously in:

• History of epilepsy or risk factors for seizures
• Diabetes mellitus (↑ risk of hypoglycemia)
• Renal impairment (↑ dosing interval recommended if CCr <30 mL/min)
• Hepatic impairment (↑ dosing interval recommended in patients with cirrhosis)
• Suicidal or prone to addiction (↑ risk of suicide)
• Excessive use of alcohol (↑ risk of suicide)
• ↑intracranial pressure or head trauma
• History of opioid dependence or recent use of large doses of opioids
• OB: Use during pregnancy only if potential maternal benefit justifies potential fetal risk
• Geri: Immediate release: Not to exceed 300 mg/day in patients >75 yr; Extended release: Use with extreme caution in patients >75 yr. ↑ risk of hyponatremia in females >65 yr.

Derm: pruritus, sweating.

EENT: visual disturbances.

Endo: hypoglycemia.

F and E: hyponatremia.

GI: constipation, nausea, abdominal pain, anorexia, diarrhea, dry mouth, dyspepsia, flatulence, vomiting.

GU: ↓fertility, menopausal symptoms, urinary retention/frequency.

Neuro: dizziness, headache, somnolence, anxiety, confusion, coordination disturbance, euphoria, hypertonia, malaise, nervousness, SEIZURES, sleep disorder, stimulation, weakness.

Resp: RESPIRATORY DEPRESSION (INCLUDING CENTRAL SLEEP APNEA AND SLEEP-RELATED HYPOXEMIA).
Misc: physical dependence, psychological dependence, tolerance.

Drug-Drug:

• MAO inhibitors↑ risk of adverse reactions; concurrent use or use within previous 14 days contraindicated.
• ↑risk of CNS depression when used concurrently with other CNS depressants, including alcohol, antihistamines, sedative/hypnotics, opioid analgesics, anesthetics, or psychotropic agents.
• Mixed agonist/antagonist analgesics, including nalbuphine or butorphanol, and partial agonist analgesics, including buprenorphine, may ↓ tramadol's analgesic effects and/or precipitate opioid withdrawal in physically dependent patients.
• ↑risk of seizures with high doses of penicillins, cephalosporins, phenothiazines, opioid analgesics, or antidepressants.
• Carbamazepine↑ metabolism and ↓ effectiveness of tramadol (increased doses may be required).
• CYP2D6 inhibitors, including quinidine, fluoxetine, paroxetine, and bupropion, may ↓ levels of active metabolite (M1) and lead to ↓ analgesic effects.
• CYP3A4 inhibitors, including erythromycin, clarithromycin, ketoconazole, itraconazole, and protease inhibitors, may allow for a greater degree of metabolism via CYP2D6 and ↑ levels of the active metabolite (M1) leading to respiratory depression.
• CYP3A4 inducers may ↓ levels and effectiveness.
• Drugs that affect serotonergic neurotransmitter systems, including SSRIs, SNRIs, MAO inhibitors, TCAs, trazodone, mirtazapine, 5-HT₃ receptor antagonists, linezolid, methylene blue, and triptans, ↑ risk of serotonin syndrome.

Drug-Natural Products:

• Concomitant use of kava-kava, valerian, or chamomile can ↑ CNS depression.
• ↑risk of serotonin syndrome when used with St. John's wort.

(Generic available)

• Immediate-release tablets: 50 mg; 100 mg;
• Extended-release capsules (Conzip): 100 mg; 200 mg; 300 mg;
• Extended-release tablets: 75 mg; 100 mg; 150 mg; 200 mg; 300 mg; 400 mg;
• Oral solution (grape flavor): 5 mg/mL;
• In combination with: acetaminophen; celecoxib (Seglentis). See Appendix [not included in this PDA edition].

Immediate Release

• PO (Adults 18 yr): Rapid titration: 50–100 mg every 4–6 hr (not to exceed 400 mg/day [300 mg in patients >75 yr]). Gradual titration: 25 mg/day initially, ↑ by 25 mg/day every 3 days to reach dose of 25 mg 4 times daily, then ↑ by 50 mg/day every 3 days to reach dose of 50 mg 4 times daily; may then use 50–100 mg every 4–6 hr (maximum dose = 400 mg/day).

Extended Release

• PO (Adults): Not currently receiving immediate-release: 100 mg once daily initially, may then titrate every 5 days up to 300 mg/day; Currently receiving immediate-release: calculate 24-hr total dose of immediate-release product and give same dose (rounded down to next lowest 100-mg increment) of ER once daily (maximum dose = 300 mg/day).

ConZip, Qdolo, Ultram, Ultram ER

• Acts as a -opioid receptor agonist.
• Inhibits reuptake of serotonin and norepinephrine in the CNS.

• Decreased pain.

Therapeutic Classification: analgesics (centrally acting), opioid analgesics

Pharmacologic Classification: opioid agonists

Absorption: Immediate-release: 75% absorbed after oral administration; Extended-release: 85–90% (compared with immediate-release).

Distribution: Crosses the placenta; enters breast milk.

Metabolism/Excretion: Mostly metabolized by the liver (primarily by the CYP2D6 and CYP3A4 isoenzymes); primarily metabolized by the CYP2D6 isoenzyme to active metabolite with analgesic activity (M1); CYP2D6 enzyme system exhibits genetic polymorphism; 7% of population may be poor metabolizers and may have significantly ↑ concentrations of tramadol and ↓ concentrations of M1 metabolite. 1–10% of Whites, 3–4% of Blacks, and 1–2% of East Asians may be CYP2D6 ultra-rapid metabolizers and have significantly ↑ concentrations of M1 metabolite. 30% eliminated unchanged in the urine.

Half-life: Tramadol (immediate release): 6–8 hr, Extended release: 7.9 hr; Active metabolite: 7–9 hr; both are ↑ in renal or hepatic impairment.

Schedule IV (C-IV)

Durela, Ralivia, Tridural, Zytram XL

(analgesia)

• REMS: Instruct patient on how and when to ask for pain medication. Do not stop taking without discussing with health care professional; may cause withdrawal symptoms if discontinued abruptly after prolonged use. Do not increase doses without discussing with health care professional; may lead to overdose. Discuss safe use, risks, and proper storage and disposal of opioid analgesics with patients and caregivers with each Rx. The Patient Counseling Guide is available at opioidanalgesicrems.com/patientCounselingGuide.html.
• May cause dizziness and drowsiness. Caution patient to avoid driving or other activities requiring alertness until response to medication is known.
• Advise patient that tramadol is a drug with known abuse potential. Protect it from theft, and never give to anyone other than the individual for whom it was prescribed. Store out of sight and reach of children, and in a location not accessible by others.
• Educate patients and caregivers on how to recognize respiratory depression and emphasize the importance of calling 911 or getting emergency medical help right away in the event of a known or suspected overdose. Inform patients and caregivers about ways to obtain naloxone as permitted by individual state naloxone dispensing and prescribing requirements or guidelines (by prescription, directly from a pharmacist, or as part of a community-based program).
• Advise patient to change positions slowly to minimize orthostatic hypotension.
• Caution patient to avoid concurrent use of alcohol or other CNS depressants, including other opioids, with this medication. Advise patient to notify health care professional before taking other RX, OTC, or herbal products concurrently.
• Advise patient to notify health care professional if seizures or if symptoms of serotonin syndrome occur.
• Encourage patient to turn, cough, and breathe deeply every 2 hr to prevent atelectasis.
• Advise patient to notify health care professional if pregnancy is planned or suspected and to avoid breastfeeding during therapy. Inform patient of potential for neonatal opioid withdrawal syndrome with prolonged use during pregnancy. Monitor neonate for signs and symptoms of withdrawal symptoms (irritability, hyperactivity and abnormal sleep pattern, high pitched cry, tremor, vomiting, diarrhea, and/or failure to gain weight); usually occur the first days after birth. Monitor infants exposed to tramadol through breast milk for excess sedation and respiratory depression. Neonatal seizures, fetal death, and still birth have been reported with tramadol immediate-release products. Chronic use may reduce fertility in females and males.
• Emphasize the importance of aggressive prevention of constipation with the use of tramadol.

TRA-ma-dol