Qdolo - Drug Monograph

Introduction

Qdolo (tramadol hydrochloride) is an opioid agonist and serotonin-norepinephrine reuptake inhibitor approved by the FDA in 2020 for the management of acute pain in adults severe enough to require an opioid analgesic and for which alternative treatments are inadequate. It represents the first FDA-approved oral tramadol solution, providing an alternative formulation for patients who have difficulty swallowing tablets.

Mechanism of Action

Qdolo exerts its analgesic effects through dual mechanisms:

• Weak μ-opioid receptor agonist activity (approximately 1/10th the potency of morphine)
• Inhibition of neuronal reuptake of serotonin and norepinephrine

The parent compound tramadol has relatively low affinity for opioid receptors, but its primary active metabolite (O-desmethyltramadol or M1) has significantly higher μ-opioid receptor affinity (approximately 200 times greater than tramadol itself). The monoamine reuptake inhibition contributes to its analgesic effects through non-opioid mechanisms.

Indications

FDA-approved for:

• Management of acute pain in adults severe enough to require an opioid analgesic
• For which alternative treatments are inadequate

• Not indicated for as-needed ("prn") analgesia
• Not for extended-release or chronic pain management
• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, reserve Qdolo for use in patients for whom alternative treatment options have not been tolerated or are not expected to be tolerated, or have not provided adequate analgesia or are not expected to provide adequate analgesia.

Dosage and Administration

• 25 mg/mL oral solution
• Recommended starting dose: 25 mg every 4-6 hours as needed for pain
• Titrate gradually to achieve adequate analgesia while minimizing adverse effects
• Maximum daily dose: 400 mg (for non-elderly adults with normal hepatic and renal function)

• Renal impairment: CrCl <30 mL/min: Maximum 200 mg daily with extended dosing interval (every 12 hours)
• Hepatic impairment: Cirrhosis: Maximum 100 mg daily with extended dosing interval (every 12 hours)
• Geriatric patients (>75 years): Maximum 300 mg daily
• CYP2D6 poor metabolizers: Reduced efficacy due to decreased formation of active M1 metabolite; consider alternative analgesia

• Use provided calibrated oral syringe for accurate dosing
• May be taken with or without food
• Measure dose precisely; do not use household teaspoons

Pharmacokinetics

• Rapidly absorbed after oral administration
• Absolute bioavailability: approximately 75%
• Time to peak concentration: 2-3 hours
• Food has minimal effect on absorption

• Volume of distribution: 2.6-2.9 L/kg
• Protein binding: approximately 20%
• Crosses placental barrier and excreted in breast milk

• Extensive hepatic metabolism via CYP pathways:

- CYP2D6: O-demethylation to active M1 metabolite - CYP3A4: N-demethylation to inactive M2 metabolite

• M1 metabolite primarily responsible for μ-opioid activity

• Half-life: tramadol: 5-7 hours; M1 metabolite: 7-9 hours
• Excretion: primarily renal (30% unchanged, 60% as metabolites)
• Total clearance: approximately 90 mL/min

Contraindications

• Significant respiratory depression
• Acute or severe bronchial asthma in unmonitored settings or absence of resuscitative equipment
• Known or suspected gastrointestinal obstruction, including paralytic ileus
• Hypersensitivity to tramadol or any component of Qdolo
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping MAOI therapy

Warnings and Precautions

• Addiction, abuse, and misuse: Risk assessment and proper prescribing required
• Life-threatening respiratory depression: Monitor closely, especially during initiation
• Neonatal opioid withdrawal syndrome: Prolonged use during pregnancy can result in withdrawal
• Risks from concomitant use with benzodiazepines or other CNS depressants

• Serotonin syndrome: Risk increased with concomitant serotonergic drugs
• Seizures: Risk increased in patients with seizure disorders or concomitant medications that lower seizure threshold
• Suicidal ideation and behavior: Monitor for depression and suicidal thoughts
• Adrenal insufficiency: Cases reported with opioid use
• Severe hypotension: Use with caution in volume-depleted patients
• Gastrointestinal effects: May cause spasm of sphincter of Oddi
• Increased intracranial pressure: Use with caution in patients with head injury

Drug Interactions

• CNS depressants: Enhanced sedative effects (benzodiazepines, alcohol, barbiturates)
• Serotonergic drugs: Increased serotonin syndrome risk (SSRIs, SNRIs, TCAs, triptans)
• MAO inhibitors: Risk of serotonin syndrome and reduced tramadol efficacy
• CYP2D6 inhibitors: Reduced formation of active M1 metabolite (quinidine, fluoxetine, paroxetine)
• CYP3A4 inhibitors/inducers: Altered tramadol metabolism (ketoconazole, rifampin)
• Carbamazepine: Reduces tramadol efficacy through CYP3A4 induction

Adverse Effects

• Nausea (30-40%)
• Constipation (25-35%)
• Headache (20-25%)
• Dizziness (15-25%)
• Somnolence (15-20%)
• Vomiting (15-20%)
• Pruritus (10-15%)

• Respiratory depression
• Seizures
• Serotonin syndrome
• Anaphylaxis
• Adrenal insufficiency
• Androgen deficiency
• Severe hypotension

Monitoring Parameters

• Pain assessment: Regular evaluation of pain relief and functional improvement
• Respiratory status: Especially during initiation and dose titration
• Mental status: Monitor for sedation, cognitive impairment
• Bowel function: Assess for constipation; implement bowel regimen
• Signs of misuse/abuse: Monitor prescribing patterns, patient behaviors
• Renal and hepatic function: Periodic assessment in patients with impairment
• Serotonin syndrome symptoms: Agitation, hallucinations, tachycardia, hyperthermia

Patient Education

• Take exactly as prescribed; do not increase dose without consulting prescriber
• Do not share medication with others
• Avoid alcohol and other CNS depressants
• May cause dizziness/drowsiness; avoid driving or operating machinery
• Report any difficulty breathing, excessive sedation, or seizures
• Manage constipation with increased fluids, fiber, and stool softeners
• Store securely away from children and others
• Proper disposal of unused medication
• Inform all healthcare providers of Qdolo use
• Do not stop abruptly; taper under medical supervision if discontinuing

References

1. FDA prescribing information: Qdolo (tramadol hydrochloride) oral solution. 2020. 2. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin Pharmacokinet. 2004;43(13):879-923. 3. Raffa RB, et al. The clinical pharmacology of tramadol. Clin Pharmacokinet. 1993;25(4):315-327. 4. Dhesi M, et al. Tramadol-induced seizures and serotonin syndrome. Am J Emerg Med. 2019;37(5):996.e5-996.e7. 5. Nelson EM, Philbrick AM. Avoiding serotonin syndrome: the art of medication reconciliation. Fed Pract. 2012;29(4):28-33. 6. Trescot AM, et al. Opioid guidelines in the management of chronic non-cancer pain. Pain Physician. 2008;11(2 Suppl):S5-S62. 7. Clinical Pharmacology [database online]. Tampa, FL: Elsevier; 2023. 8. Micromedex Solutions. Tramadol. Truven Health Analytics, 2023.