TRA-ma-dol

Therapeutic Classification: analgesics (centrally acting), opioid analgesics

Pharmacologic Classification: opioid agonists

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

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

• Decreased pain.

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.

(analgesia)

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.

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).

(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].

• Assess type, location, and intensity of pain before and 2–3 hr (peak) after administration.
• Assess BP and respiratory rate before and periodically during administration. Respiratory depression has not occurred with recommended doses.
• Assess bowel function routinely. Prevention of constipation should be instituted with increased intake of fluids and bulk and with laxatives to minimize constipating effects. Administer stimulant laxatives routinely if opioid use exceeds 2–3 days, unless contraindicated. Consider drugs for opioid-induced constipation.
• Prolonged use may lead to physical and psychological dependence and tolerance, although these may be milder than with other opioids. This should not prevent patient from receiving adequate analgesia. Patients who receive tramadol for pain rarely develop psychological dependence. If tolerance develops, changing to an opioid agonist may be required to relieve pain. Prolonged use of opioids should be reserved for patients whose pain remains severe enough to require them and alternative treatment options continue to be inadequate. Many acute pain conditions treated in the outpatient setting require no more than a few days of an opioid pain medicine.
• Monitor for signs and symptoms of hyponatremia (confusion, disorientation) during therapy, especially during early therapy. If signs and symptoms of hyponatremia occur, begin treatment (fluid restriction) and discontinue tramadol.
• Monitor patient for seizures. May occur within recommended dose range. Risk is increased with higher doses and in patients taking antidepressants (SSRIs, SNRIs, TCAs, or MAO inhibitors), opioid analgesics, or other drugs that decrease the seizure threshold. Also monitor for serotonin syndrome (mental-status changes [e.g., agitation, hallucinations, coma], autonomic instability [e.g., tachycardia, labile BP, hyperthermia], neuromuscular aberrations [e.g., hyperreflexia, incoordination] and/or GI symptoms [e.g., nausea, vomiting, diarrhea] in patients taking these drugs concurrently).
• Assess risk for opioid addiction, abuse, or misuse prior to administration. Abuse or misuse of extended-release preparations by crushing, chewing, snorting, or injecting dissolved product will result in uncontrolled delivery of tramadol and can result in overdose and death.

• May cause ↑ serum creatinine, ↑ liver enzymes, ↓ hemoglobin, and proteinuria.
  • May cause hyponatremia and hypoglycemia. Monitor blood glucose levels in patients with predisposing risk factors, including diabetes, renal insufficiency, or in elderly patients.

• Overdose may cause respiratory depression and seizures. Naloxone may reverse some, but not all, of the symptoms of overdose. Treatment should be symptomatic and supportive. Maintain adequate respiratory exchange. Hemodialysis is not helpful because it removes only a small portion of administered dose. Seizures may be managed with barbiturates or benzodiazepines; naloxone increases risk of seizures.

• Do not confuse tramadol with trazodone.
  • Tramadol is considered to provide more analgesia than codeine 60 mg but less than combined aspirin 650 mg/codeine 60 mg for acute postoperative pain.
  • For chronic pain, daily doses of 250 mg of tramadol provide pain relief similar to that of 5 doses/day of acetaminophen 300 mg/codeine 30 mg, 5 doses/day of aspirin 325 mg/codeine 30 mg, or 2–3 doses/day of acetaminophen 500 mg/oxycodone 5 mg.
  • Explain therapeutic value of medication before administration to enhance the analgesic effect.
  • Regularly administered doses may be more effective than as-needed administration. Analgesic is more effective if given before pain becomes severe.
  • Tramadol should be discontinued gradually after long-term use to prevent withdrawal symptoms. For patients on long-acting agents who are physically opioid-dependent, initiate the taper by a small enough increment (no greater than 10%–25% of total daily dose) to avoid withdrawal symptoms, and proceed with dose-lowering at an interval of every 2–4 wk. Patients who have been taking opioids for briefer periods of time may tolerate a more rapid taper. Monitor frequently to manage pain and withdrawal symptoms (restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, or increased blood pressure, respiratory rate, or heart rate). If withdrawal symptoms occur, pause the taper for a period of time or raise the dose of opioid analgesic to the previous dose, and then proceed with a slower taper. Also, monitor patients for changes in mood, emergence of suicidal thoughts, or use of other substances. A multimodal approach to pain management may optimize the treatment of chronic pain, as well as assist with the successful tapering of the opioid analgesic.
• PO: Tramadol may be administered without regard to meals. DNC: Swallow extended-release tablets and capsules whole; do not crush, break, dissolve, or chew.
• REMS: FDA strongly encourages health care professionals to complete a REMS-compliant education program that includes all the elements of the FDA Education Blueprint for Health Care Providers Involved in the Management or Support of Patients with Pain, available at OpioidAnalgesicREMSBlueprint. Information on programs can be found at 1-800-503-0784 or .
• Discuss availability of naloxone for emergency treatment of opioid overdose with the patient and caregiver and assess the potential need for access to naloxone, both when initiating and renewing therapy, especially if patient has household members (including children) or other close contacts at risk for accidental exposure or overdose. Consider prescribing naloxone, based on the patient’s risk factors for overdose, such as concomitant use of CNS depressants, a history of opioid use disorder, or prior opioid overdose. However, the presence of risk factors for overdose should not prevent the proper management of pain in any patient.

• 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.

• Decrease in severity of pain without a significant alteration in level of consciousness or respiratory status.

ConZip, Qdolo, Ultram, Ultram ER

Durela, Ralivia, Tridural, Zytram XL

Schedule IV (C-IV)