Version May 2024
The FDA has issued a drug safety communication to announce safety-related updates to the prescribing information for immediate-release (IR) and extended-release (ER)/long-acting (LA) opioid analgesics, including updates to Boxed Warnings, Indications and Usage, Dosage and Administration, Warnings and Precautions, and the Medication Guide. These safety labeling changes are intended to provide clarity on appropriate patient populations for opioid treatment, appropriate dosage and administration, and updated information on the risks associated with opioid use. The required safety labeling changes include stating:
the risk of overdose increases as the dosage increases for all opioid pain medicines;
IR opioids should not be used for an extended period of time unless a patient's 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;
it is recommended to reserve ER/LA opioid pain medicines for severe and persistent pain that requires an extended treatment period with a daily opioid pain medicine and for which alternative treatment options are inadequate; and
a warning about opioid-induced hyperalgesia (OIH), including information on differentiating OIH symptoms from those of opioid tolerance and withdrawal.
Further information may be found at https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-prescribing-information-all-opioid-pain-medicines-provide-additional-guidance-safe-use.
Because the use of hydromorphone 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 or conditions.
Extended-release tablets, immediate-release tablets, oral solution: 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 hydromorphone, especially during initiation or following a dosage increase. To reduce the risk of respiratory depression, proper dosing and titration of hydromorphone are essential.
Accidental ingestion of even one dose of hydromorphone, especially by children, can result in a fatal overdose of hydromorphone.
If opioid use is required for an extended period of time in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome (NOWS), which may be life threatening if not recognized and treated. Ensure that management by neonatology experts will be available at delivery.
Injection: High-potency hydromorphone (10 mg/mL) is a more concentrated solution of hydromorphone than hydromorphone 1, 2, or 4 mg/mL, and is for use in opioid-tolerant patients only. Do not confuse high-potency hydromorphone with standard parenteral formulations of hydromorphone or other opioids, as overdose and death could result.
Oral solution: Ensure accuracy when prescribing, dispensing, and administering hydromorphone oral solution. Dosing errors due to confusion between mg and mL, and other hydromorphone oral solutions of different concentrations can result in accidental overdose and death.
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 hydromorphone and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
Dosage guidance:
Safety: Consider prescribing naloxone 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 [equivalent to ≥12.5 mg oral hydromorphone/day]), and/or concomitant benzodiazepine use (Ref).
Dosing: Dosing provided is based on typical doses; some patients may require higher or lower doses. Individualize dosing based on patient-specific factors (eg, comorbidities, severity of pain, 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.
Clinical considerations: Opioids may be part of a comprehensive, multimodal, patient-specific treatment plan for managing severe pain. Maximize nonopioid analgesia (when appropriate) prior to initiation of opioid analgesia (Ref).
Acute pain in opioid-naive patients:
General dosing: Note: For acute non–cancer-related pain severe enough to require an opioid, utilize multimodal pain control, maximize nonopioid analgesics, and limit the quantity prescribed to the expected duration of pain severe enough to require opioids. Do not use long-acting preparations for treatment of acute pain (Ref).
Oral: Opioid-naive patients:
Immediate release: Oral: Initial: 1 to 2 mg every 4 to 6 hours as needed; adjust dose according to patient response. Usual dosage range: 1 to 4 mg every 4 to 6 hours as needed. If usual dose and frequency is insufficient, reassess patient and reconsider pain management strategies. For outpatient use, usually up to 8 mg/day for moderate pain or up to 12 mg/day for severe pain will suffice (Ref).
IV: Opioid-naive patients:
Note: Highly concentrated 10 mg/mL (hydromorphone HP) formulation is not for use in patients who are opioid naive.
Intermittent dosing: IV: Initial: 0.2 to 0.5 mg every 2 to 4 hours as needed; adjust dose according to patient response under close monitoring. Usual dosage range: 0.2 to 1 mg every 2 to 4 hours as needed. If usual dose and frequency is insufficient, reassess patient and reconsider pain management strategies (Ref).
Patient-controlled analgesia:
Note: Reserve for use in patients who are alert and have the capacity to repeatedly press a button to titrate analgesia (eg, postoperatively). Initiate patient-controlled analgesia only after initial pain control is achieved (Ref).
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a May adjust dosing and provide rescue bolus doses (eg, 0.1 to 0.3 mg) if analgesia is inadequate (Buys 2023). | |
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b The use of a continuous basal infusion for patient-controlled analgesia is generally not recommended for most patients because of the risk of respiratory depression, and use should be limited to carefully selected patients who are opioid tolerant and/or receiving care in an ICU (Buys 2023). | |
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Usual concentration |
0.2 mg/mL |
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Demand dose |
Usual range: 0.1 to 0.3 mga |
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Basal dose |
In general, a continuous (basal) infusion is not recommended in an opioid-naive patient (ISMP 2009)b |
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Lockout interval |
10 to 20 minutes |
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Maximum cumulative dose |
6 mg within a 4-hour period |
IM, SUBQ: Opioid-naive patients:
Note: Not recommended for routine use. Reserve for patients without IV or oral access. IM administration is generally not recommended due to pain associated with injection, variable absorption, and delayed time to peak effect (Ref). Although SUBQ absorption is ~80% of the IV route, some experts use a 1:1 (SUBQ:IV) ratio for dosing (Ref).
IM, SUBQ: Initial: 0.2 to 0.5 mg every 2 to 3 hours as needed; adjust dose according to patient response under close monitoring. If usual dose and frequency is insufficient, reassess patient and reconsider pain management strategies.
Rectal: Opioid-naive patients:
Note: May be used as an alternative to IV or oral administration.
Rectal: Initial: 3 mg (1 suppository) every 6 to 8 hours as needed.
Acute pain in opioid-tolerant patients (eg, breakthrough cancer pain):
Oral, IV, SUBQ: Usual dose: In conjunction with the scheduled long-acting opioid, administer 5% to 15% (rarely up to 20%) of the 24-hour hydromorphone requirement (or MME) as needed using an IR or parenteral formulation every 3 to 6 hours with subsequent dosage adjustments based on response (Ref). Note: If chronic opioid is not hydromorphone, use MME calculations cautiously due to lack of complete cross-tolerance; generally, reduce calculated dose by 25% to 50%. Conversions from methadone are highly variable and require extreme caution (Ref).
Acute postoperative pain, postoperative recovery/postanesthesia care unit:
Note: Optimize multimodal perioperative pain management (eg, regional or local anesthesia, nerve blocks, nonopioid analgesics, and other adjuvants) to minimize opioid use (Ref). Refer to institutional protocols.
Initial pain control:
IV: Initial: 0.2 to 0.5 mg given as frequently as every 5 minutes until adequate pain relief or adverse effects (eg, respiratory depression, oxygen desaturation, hypotension) occur (Ref). Refer to institution-specific protocols as appropriate.
Ongoing pain control:
IV, SUBQ: 0.2 to 0.5 mg every 3 to 4 hours as needed. If usual dose and frequency is insufficient, reassess patient and reconsider pain management strategies. Note: If IV access is difficult, may administer SUBQ (Ref). Although SUBQ absorption is ~80% of the IV route, some experts use a 1:1 (SUBQ:IV) ratio for dosing (Ref).
Note: If patient-controlled analgesia is needed, refer to "Example Hydromorphone IV Patient-Controlled Analgesia Initial Dose Ranges for Patients Who Are Opioid Naive" table.
Acute vaso-occlusive pain in sickle cell disease:
Note: Dosing presented is for patients who do not have a pain treatment plan on file and whose previous opioid dose for prior episodes is unknown. Refer to the individual's personal pain protocol or institutional pain protocol for dosing if available. If opioid dose given for a prior episode is known, choose initial dose based on intensity of pain in comparison with previous episode and previous effective dose (Ref).
Unknown pain treatment plan:
Patient weight ≥50 kg:
IV: Initial: 1.5 mg, given once within 30 to 60 minutes of presentation; if severe pain continues, repeat with ~20% to 50% of the original dose every ~30 minutes; monitor for sedation/respiratory depression (Ref).
Patient weight <50 kg:
IV: Initial: 0.02 to 0.05 mg/kg (maximum initial dose: 1.5 mg), given once within 30 to 60 minutes of presentation; if severe pain continues, repeat with ~20% to 50% of the original dose every ~30 minutes; monitor for sedation/respiratory depression (Ref).
Note: If IV access is difficult, may administer SUBQ (Ref). Although SUBQ absorption is ~80% of the IV route, some experts use a 1:1 (SUBQ:IV) ratio for dosing (Ref).
Chronic pain, noncancer and cancer pain:
Note: Before starting opioid therapy for chronic pain, establish realistic goals for pain and function, and consider how therapy will be discontinued if benefits do not outweigh risks (Ref). Opioids, including hydromorphone, 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 chronic pain from active cancer, sickle cell disease, and end-of-life care. Consider opioids, including hydromorphone, only in patients who experience clinically meaningful improvement in pain and function that outweighs patient safety risks (Ref).
Opioid-naive patients: Noncancer or cancer pain:
Note: For noncancer pain, establish hydromorphone requirement using IR formulations (Ref). In patients with cancer pain, may switch to a long-acting formulation earlier in the course of therapy (Ref).
Immediate release: Oral: Initial: 1 to 2 mg every 3 to 4 hours as needed or scheduled around the clock (eg, cancer pain); adjust dose according to patient response (see "Titration" below). Usual dosage range: 1 to 4 mg every 3 to 4 hours as needed or scheduled around the clock. If usual dose and frequency is insufficient, reassess patient and reconsider pain management strategies (Ref).
Titration:
Noncancer pain: Adjust dose according to patient response. If needed, increase the dose slowly in increments of no more than 25% to 50% of the total daily dose (Ref). Note: Dosages ≥50 MME/day (equivalent to ≥12.5 mg oral hydromorphone/day) are likely to not have increased benefits in pain relief or function relative to overall risks. To reduce risk of overdose in noncancer pain (excluding patients with sickle cell disease and palliative care), readdress pain and reassess evidence of individual benefits and risks when increasing opioid dosage to ≥50 MME/day (equivalent to ≥12.5 mg oral hydromorphone/day) (Ref).
Cancer pain: Adjust dose according to patient response. If needed, increase the fixed scheduled dose by 30% to 100% of the total dose taken in the prior 24-hour period, while taking into consideration the total amount of rescue medication used (Ref).
Extended release: Oral:
Note: Do not use in opioid-naive, noncancer patients with chronic pain until treated for at least 1 week with IR form. Unless pain is associated with cancer, palliative care, or sickle cell disease, reserve ER opioids for patients who have received IR opioids daily for ≥1 week yet continue to experience severe, continuous pain (Ref).
Capsules, controlled release, 12 hour (Hydromorph Contin [Canadian product]): Oral: Initial: 3 mg every 12 hours; increase dose every 48 hours as needed; maximum total daily dose: 18 mg/day for noncancer, nonpalliative pain.
IV, SUBQ:
Note: Typically reserved for acute exacerbations or for patients who cannot tolerate oral administration. For progressive illnesses (eg, cancer), a continuous IV or SUBQ infusion, with or without a patient-controlled analgesia option, can also be used as pain requirements increase. In general, SUBQ dose is equivalent to IV dose (Ref). Individualize dose based on patient's previous opioid intake and appropriate opioid analgesic equivalents; titrate further, if needed, based on level of pain.
IV, SUBQ: Initial: 0.2 to 0.4 mg every 2 to 4 hours as needed; adjust dose according to patient response. Usual maintenance dosage range: 0.2 to 1 mg every 2 to 4 hours as needed (Ref). If usual dose and frequency is insufficient, reassess patient and reconsider pain management strategies. Refer to institutional protocols; reported dosing varies widely based on practice and patient needs (Ref).
Opioid-tolerant patients: Noncancer or cancer pain (also refer to the section "Dose Conversions for Pain Management" ):
Oral: Extended release:
Note: Do not use in opioid-naive, noncancer patients with chronic pain until treated for at least 1 week with IR form. Unless pain is associated with cancer, palliative care, or sickle cell disease, reserve ER opioids for patients who have received IR opioids daily for ≥1 week yet continue to experience severe, continuous pain (Ref).
Capsules, controlled release, 12 hour (Hydromorph Contin [Canadian product]):
Note: Capsule strengths ≥18 mg or a single dose >12 mg should be reserved for use only in patients who are opioid tolerant requiring oral hydromorphone dosages ≥36 mg daily (or equivalent).
Individualization of dose: Oral: Administer total daily oral hydromorphone dose in 2 divided doses (every 12 hours).
Tablets, extended release, 24 hour: Oral:
Individualization of dose: See "Dose Conversions for Pain Management." Discontinue or taper all other ER and around-the-clock opioids when starting therapy. Refer to published equianalgesic opioid conversion data for guidance (or refer to institutional protocols), then administer estimated total daily oral hydromorphone dose once daily. Note: When selecting the initial dose, other characteristics (eg, patient condition; degree of opioid tolerance; concurrent medications; type of pain; risk factors for substance use disorder, abuse, and misuse) should also be considered. Pain relief and adverse events should be assessed frequently.
Initial sample dose: Estimated total daily oral hydromorphone dose once daily (eg, 8 mg once daily).
Titration and maintenance: Dose adjustments in 4 to 8 mg increments may occur every 3 to 4 days. In patients experiencing breakthrough pain, consider increasing the dose of ER hydromorphone or providing rescue medication of an IR analgesic at an appropriate dose. Do not administer ER hydromorphone more frequently than once every 24 hours. Dosages ≥50 MME/day (equivalent to ≥12.5 mg oral hydromorphone/day) are likely to not have increased benefits in pain relief or function relative to overall risks. To reduce risk of overdose in noncancer and nonpalliative pain, readdress pain and reassess evidence of individual benefits and risks when increasing opioid dosage ≥50 MME/day orally (equivalent to ≥12.5 mg oral hydromorphone/day) (Ref).
Neuraxial analgesia: Note: Reserve use for severe pain (eg, after surgery). Must be administered by health care providers skilled in the care of patients receiving intraspinal opioids (Ref). Use a preservative-free formulation intended for neuraxial use.
Epidural:
Note: Example regimens and usual doses are provided; specific regimens and doses vary based on type of surgery, comorbidities, and institutional policies and practices.
Single dose: Opioid-naive patients: Epidural: Usual dosage range: 0.4 to 1.5 mg (Ref).
Continuous infusion: Opioid-naive patients: Epidural: Usual dosage range: 20 to 300 mcg/hour (Ref). May be given alone or usually in combination with local anesthetics (eg, bupivacaine, ropivacaine); when combined with local anesthetic, analgesic effect is increased due to synergy (Ref).
Intrathecal:
Note: Intrathecal dose is usually 1/10 (one-tenth) that of epidural dosage (Ref).
Single dose: Intrathecal: Dosage range: 50 to 200 mcg (Ref). Note: Doses vary depending on the clinical scenario and other medications administered as part of multimodal analgesia.
Pain and sedation; critically ill patients in the ICU (off-label use):
Note: Employ multimodal approaches (eg, a combination of analgesics, including adjunctive nonopioid agents, and techniques) for pain control in this setting. Monitor pain using validated scales (eg, behavioral pain scale, critical-care observation tool) in ICU patients who are unable to self-report. Intermittent as-needed therapy is preferred where appropriate (Ref).
Intermittent dosing:
IV: Initial: 0.2 to 1 mg every 1 to 3 hours as needed; titrate to clinical effect (ie, pain control or sedation) (Ref).
Continuous IV infusion (alternative therapy): Note: May be used for breakthrough pain/sedation in patients receiving opioids or to transition from another opioid (eg, tolerance) (Ref).
IV: After initial intermittent dose (see "Intermittent Dosing"), begin continuous infusion with an initial dose of 0.5 to 2 mg/hour; titrate to clinical effect (ie, pain control and/or sedation); usual dosage range: 0.25 to 4 mg/hour (Ref).
Dose conversions to/from IR products for pain management:
Note: Equianalgesic conversions serve only as a general guide to estimate opioid dose equivalents. Multiple factors must be considered for safely individualizing conversion of opioid analgesia. In general, for noncancer pain, the decision to convert from an IR to an ER formulation should be individualized and reserved for those with severe, continuous pain who have been taking opioids for ≥1 week (Ref).
Converting from oral IR hydromorphone to parenteral hydromorphone: Approximate equivalency: 7.5 mg (oral hydromorphone): 1.5 mg (IV/SUBQ hydromorphone) (Ref).
Converting from oral IR hydromorphone to rectal hydromorphone: The bioavailability of rectal hydromorphone is ~33% of oral hydromorphone; however, absorption is variable and may be higher or lower than expected. Therefore, when switching from oral to rectal dosing, an increase in rectal dose and decrease in frequency (eg, every 6 to 8 hours) may be necessary (Ref).
Converting to/from hydromorphone (parenteral or oral) to/from a different opioid (parenteral or oral): It is safer to underestimate a patient's daily oral requirement and provide breakthrough pain relief with IR formulations rather than risk overestimating daily requirements. When switching to a new opioid (except to/from methadone), reduce initial daily calculated equianalgesic dose of the new opioid by 25% to 50% to adjust for lack of complete mu receptor cross-tolerance (conversions to/from methadone are highly variable and require extreme caution) (Ref).
Dose conversions to ER products for pain management:
Individualization of dose: Refer to published equianalgesic opioid conversion data for guidance (or refer to institutional protocols). When selecting the initial dose, other characteristics (eg, patient condition; degree of opioid tolerance; concurrent medications; type of pain; risk factors for substance use disorder, abuse, and misuse) should also be considered. Pain relief and adverse events should be assessed frequently.
Converting from oral IR hydromorphone to oral ER hydromorphone preparations:
ER tablets: Total daily oral hydromorphone dose administered once daily.
ER capsules (Hydromorph Contin [Canadian product]): Total daily oral hydromorphone dose may be administered in 2 divided doses (every 12 hours).
Converting from transdermal fentanyl to hydromorphone ER 24-hour tablets: Treatment with hydromorphone ER 24 hour can be started 18 hours after the removal of the transdermal fentanyl patch. For every fentanyl 25 mcg/hour transdermal dose, the estimated equianalgesic dose of hydromorphone ER is 12 mg every 24 hours. Due to incomplete cross-tolerance, an appropriate starting dose is 50% of the calculated total daily dose given every 24 hours (Example: fentanyl 50 mcg/hour transdermal dose = hydromorphone ER 24 mg/day, then divide in half the calculated hydromorphone ER dose: patient hydromorphone ER dose is 12 mg/day). If necessary, round down to the appropriate hydromorphone ER tablet strength available.
Converting from other opioids to hydromorphone ER 24-hour tablets: Refer to published equianalgesic opioid conversion data for guidance (or refer to institutional protocols). Conversion ratios are only approximations and substantial interpatient variability exists; therefore, it is safer to underestimate a patient's daily oral requirement and provide breakthrough pain relief with IR formulations rather than risk overestimating daily requirements. When switching to a new opioid (except to/from methadone), reduce initial daily calculated equianalgesic dose of the new opioid by 25% to 50% to adjust for lack of complete mu receptor cross-tolerance (conversions to/from methadone are highly variable and require extreme caution) (Ref).
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. 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).
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.
Note: Approximately 37% of a hydromorphone dose is recovered in the urine as hydromorphone-3-glucuronide, a potentially neuroexcitatory metabolite that can accumulate with kidney impairment (Ref). Careful titration of dosing with close monitoring of response and adverse reactions (eg, CNS depression, respiratory depression, neuroexcitation) due to drug and metabolite accumulation is important with all degrees of kidney impairment.
Injection, oral, rectal:
Altered kidney function (expert opinion derived from manufacturer’s labeling) (Ref):
CrCl ≥60 mL/minute: No dosage adjustment necessary.
CrCl 30 to <60 mL/minute: Administer 50% of usual initial dose.
CrCl <30 mL/minute:
Immediate release: Administer 25% of usual initial dose and extend dosing interval by 25% to 50%.
Extended release: ER opioids are preferably avoided due to increased risk of adverse effects and toxicity (Ref). If necessary, administer 25% of usual initial dose. Alternatively, as hydromorphone ER tablets are only intended for once daily administration, consider switching to IR tablets or another analgesic that will permit more flexibility with the dosing interval (Ref).
Hemodialysis, intermittent (thrice weekly): Dialyzable (both hydromorphone [~55%] (Ref) and its hydromorphone-3-glucuronide metabolite [exact % removed unknown] (Ref)):
Immediate release: Administer 25% of usual initial dose and extend dosing interval by 25% to 50% (Ref).
Extended release: Avoid use (Ref).
Peritoneal dialysis:
Immediate release: Administer 25% of usual initial dose and extend dosing interval by 25% to 50% (Ref).
Extended release: Avoid use (Ref).
CRRT: Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement. Recommendations are based on high-flux dialyzers and effluent flow rates of 20 to 25 mL/kg/hour (or ~1,500 to 3,000 mL/hour) unless otherwise noted.
Immediate release: Administer 25% to 50% of usual initial dose and extend the dosing interval by 25% to 50% (Ref).
Extended release: Avoid use (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): Note: Drug clearance is dependent on the effluent flow rate, filter type, and method of renal replacement.
Immediate release: Administer 25% to 50% of the usual initial dose and extend the dosing interval by 25% to 50% (Ref).
Extended release: Avoid use (Ref).
Injectable:
Mild impairment: There are no dosage adjustments provided in the manufacturer's labeling.
Moderate impairment: Initiate with 25% to 50% of the usual starting dose depending on the degree of impairment; monitor closely during dose titration.
Severe impairment: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); take into consideration when selecting a starting dose that a further increase in Cmax and AUC is expected.
Oral (immediate release), rectal: Mild to severe impairment: Initiate with 25% to 50% of the usual starting dose depending on the degree of impairment. Use with caution and regularly evaluate during dose titration. Has not been studied in severe impairment; take into consideration when selecting a starting dose that a further increase in Cmax and AUC is expected.
Oral (extended-release tablet): Hydromorphone ER:
Mild impairment: There are no dosage adjustments provided in the manufacturer's labeling.
Moderate impairment: Initiate with 25% of the usual starting dose for patients with normal hepatic function. Use with caution and monitor closely for respiratory and CNS depression.
Severe impairment: Use alternate analgesic.
Oral (extended-release capsule): Hydromorph Contin [Canadian product]:
Mild impairment: There are no dosage adjustments provided in the manufacturer's labeling; use with caution and monitor for respiratory and CNS depression.
Moderate impairment: Initiate at 25% of initial dose for normal hepatic function; titrate cautiously. Monitor closely for respiratory and CNS depression following initiation of therapy and during titration.
Severe impairment: Use is not recommended (has not been studied); consider alternative analgesics. If therapy with hydromorphone is initiated, the manufacturer recommends a more conservative dose than that recommended for moderate impairment but does not provide specific dosing recommendations. Monitor closely for respiratory and CNS depression.
Note: Minimize opioid use in older adults unless for the management of severe acute pain. Opioids are associated with an increased risk of falls and inducing or worsening delirium in older adults (Ref).
Pain management: Note: Opioids should always be used with caution in older adults due to the potential for drug accumulation and increased sensitivity to CNS active medications; monitor closely for opioid-induced adverse effects (eg, respiratory depression, hypotension, sedation) during use, particularly during treatment initiation and dose titration (Ref). Initiate doses at a low dose and titrate slowly to appropriate analgesic effects. When changing routes of administration, oral doses and parenteral doses are NOT equivalent; parenteral doses are up to 5 times more potent. Therefore, when administered parenterally, one-fifth of the oral dose will provide similar analgesia.
Oral:
IR tablets: Opioid-naive patients with persistent pain: Initial: 1 to 2 mg every 3 to 4 hours as needed (Ref). In patients >70 years of age, the American Pain Society suggests lowering initial doses by 25% to 50%, followed by upward or downward titration (Ref).
ER products: Opioid-tolerant patients only: Limited data available; based on expert opinion: After 3 to 7 days, divide the 24-hour dose requirement for IR hydromorphone into 1 or 2 doses (depending on ER product selected) (Ref).
IV:
Opioid-naive patients with persistent pain: Initial: IV: 0.2 mg every 2 to 3 hours as needed (manufacturer's labeling) or 0.25 to 0.5 mg every 3 to 4 hours as needed (limited data available; based on expert opinion). In patients >70 years of age, the American Pain Society recommends giving consideration to lowering initial doses by 25% to 50%, followed by upward or downward titration (Ref).
Opioid-naive patients in acute, severe pain: Emergency Department (ED) setting: Limited data available; one trial used the following study protocol: 0.5 mg IV given as a single dose, followed by an optional repeat dose of 0.5 mg IV 15 minutes later if patient still in pain (Ref).
IM: IM administration is not recommended and should be avoided (Ref).
(For additional information see "Hydromorphone: Pediatric drug information")
Acute pain, moderate to severe: Limited data available (Ref): Note: Doses should be titrated to appropriate analgesic effects, while minimizing adverse effects; when changing routes of administration, note that oral doses are less than one-half as effective as parenteral doses (may be only 1/5 as effective):
Infants >6 months weighing >10 kg (Ref):
Oral: Immediate release: Usual initial: 0.03 mg/kg/dose every 4 hours as needed; usual range: 0.03 to 0.06 mg/kg/dose.
IV: Usual initial: 0.01 to 0.015 mg/kg/dose every 3 to 6 hours as needed.
Continuous IV infusion: Usual initial: 0.003 to 0.005 mg/kg/hour.
Children weighing <50 kg and Adolescents weighing <50 kg:
Oral: Immediate release: 0.03 to 0.08 mg/kg/dose every 3 to 4 hours as needed; Note: The American Pain Society (2016) recommends an initial oral dose of 0.06 mg/kg for severe pain in children.
IV: 0.015 mg/kg/dose every 3 to 6 hours as needed.
Continuous IV infusion: Usual initial: 0.003 to 0.005 mg/kg/hour (maximum initial rate: 0.2 mg/hour) (Ref).
Children weighing ≥50 kg and Adolescents weighing ≥50 kg:
Oral: Immediate release: Initial: Opioid-naive: 1 to 2 mg every 3 to 4 hours as needed; patients with prior opioid exposure may tolerate higher initial doses; usual adult dose: 2 to 4 mg; doses up to 8 mg have been used in adults.
IV: Initial: Opioid-naive: 0.2 to 0.6 mg every 2 to 4 hours as needed; patients with prior opioid exposure may tolerate higher initial doses.
Continuous IV infusion: Usual infusion: 0.3 mg/hour (Ref).
IM, SubQ: Note: IM use may result in variable absorption and a lag time to peak effect. Initial: Opioid-naive: 0.8 to 1 mg every 4 to 6 hours as needed; patients with prior opioid exposure may require higher initial doses; usual dosage range: 1 to 2 mg every 3 to 6 hours as needed.
Rectal: 3 mg (1 suppository) every 6 to 8 hours as needed (Ref).
Continuous analgesia/sedation; mechanically ventilated: Limited data available: Not routinely used first-line: Infants, Children, and Adolescents: Continuous IV infusion: Initial rate: 0.018 mg/kg/hour; titrate carefully to effect; maximum reported rate: 0.043 mg/kg/hour (Ref).
Continuous analgesia/sedation; mechanically ventilated and during ECMO: Very limited data available: Not routinely used first-line: Infants and Children: Continuous IV infusion: Reported initial rate: 0.064 mg/kg/hour; titrate carefully to effect; maximum reported rate: 0.14 mg/kg/hour; dosing based on retrospective data from experience in 12 patients reported significantly higher requirements in those receiving ECMO than non-ECMO patients (Ref).
Patient-controlled analgesia (PCA): Limited data available (Ref): Opioid-naive: Note: PCA has been used in children as young as 4 years of age; however, clinicians need to assess children 4 to 8 years of age to determine if they are able to use the PCA device correctly (Ref). All patients should receive an initial loading dose of an analgesic (to attain adequate control of pain) before starting PCA for maintenance. Adjust doses, lockouts, and limits based on required loading dose, age, state of health, and presence of opioid tolerance. Use lower end of dosing range for opioid-naive; a continuous (basal) infusion is not recommended in opioid-naive patients (Ref). Assess patient and pain control at regular intervals and adjust settings if needed:
Children ≥5 years weighing <50 kg and Adolescents weighing <50 kg:
Usual concentration: 0.2 mg/mL.
Demand dose: Usual initial: 0.003 to 0.004 mg/kg/dose; usual range: 0.003 to 0.005 mg/kg/dose.
Lockout: Usual initial: 5 doses/hour.
Lockout interval: Range: 6 to 10 minutes.
Usual basal rate: 0 to 0.004 mg/kg/hour.
Children weighing ≥50 kg and Adolescents weighing ≥50 kg:
Usual concentration: 0.2 mg/mL.
Demand dose: Usual initial: 0.1 to 0.2 mg; usual range: 0.05 to 0.4 mg.
Lockout interval: Usual initial: 6 minutes; usual range: 5 to 10 minutes.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no pediatric-specific recommendations; based on experience in adult patients, dosage adjustment is suggested.
There are no pediatric-specific recommendations; based on experience in adult patients, dosage adjustment is suggested.
Opioid-induced constipation (OIC) is the most common subtype of opioid-induced bowel dysfunction, which is a broader term that encompasses additional GI opioid-induced adverse reactions including nausea, vomiting, and gastroesophageal reflux. Symptoms of OIC may include decreased frequency of bowel movements, straining to pass bowel movements, a sense of incomplete evacuation, and/or hard stools (Ref). Tolerance does not develop to OIC (Ref). Symptoms are reversible after discontinuation of the opioid (Ref). OIC is the most common reason for discontinuation reported by patients and may often result in a longer hospital stay and increased overall healthcare costs (Ref). Opioid dose or route of administration do not appear to alter risk (Ref).
Mechanism: Time-related; mu-opioid receptor stimulation in the GI tract results in delayed gastric emptying, decreased peristalsis, decreased water and chloride secretion into the intestinal lumen, and slowed bowel motility (Ref).
Onset: Varied; changes in peristalsis may occur 5 to 25 minutes after administration of opioids (Ref). However, OIC is defined based on a 7-day period of change (Ref).
Risk factors:
• Increased dosing frequency (ie, daily vs 2 to 3 times per week) (Ref)
• Chronic opioid administration (Ref)
• Concurrent use of other medications that cause constipation
Opioid-induced neurotoxicity is an opioid-related adverse drug reaction more commonly associated with opioids that have active metabolites (eg, codeine, hydromorphone, meperidine, morphine, oxycodone). Symptoms may include allodynia, delirium, hallucinations, hyperalgesia, hypersomnolence, myoclonus, tremor, and seizures (Ref).
Mechanism: Not clearly established; hypothesized to result from an accumulation of neuroexcitatory opioid metabolites (Ref).
Risk factors:
• High opioid dosage (Ref)
• Dehydration (Ref)
• Kidney failure (Ref)
• Infection (Ref)
• Older age (Ref)
Reversible peripherally- and/or centrally-mediated opioid-induced pruritus (OIP) may occur with systemic or neuraxial (ie, epidural or intrathecal) opioid administration though, it is most common with neuraxial delivery (Ref). OIP may occur less frequently with IV hydromorphone than IV morphine (Ref).
Mechanism: Dose-related; central OIP (neuraxial administration) is a result of stimulation of mu- opioid receptors in the spinal cord and brain (Ref). Peripheral OIP (systemic administration) is a result of opioid-induced nonimmunologic histamine release from mast cells (Ref).
Onset: Rapid; OIP occurred within 1 to 3 hours of neuraxial administration (data with morphine) (Ref).
Risk factors:
• Higher doses (Ref)
• Route of administration: Neuraxial > IV > oral (Ref)
• Peripartum neuraxial administration (Ref)
• Neuraxial administration in major orthopedic surgery (Ref)
• Use of extended-release formulations (Ref)
Serious, life-threatening, or fatal opioid-induced respiratory depression (OIRD) may occur with use of hydromorphone in adult and pediatric patients. Effects include hypoventilation, hypoxia, hypercapnia and respiratory acidosis, as well as reduced ventilatory responses to hypoxia and hypercapnia (Ref).
Mechanism: Dose-related; stimulation of mu-opioid receptors in the brainstem leads to suppression of the respiratory control network and depression of normal hypoxic and hypercapnic ventilatory responses (Ref).
Onset: Rapid; OIRD reported within 15 minutes of hydromorphone IV bolus administration (Ref).
Risk factors:
• Higher doses (Ref)
• Higher doses of intraoperative opioids (ie, morphine-equivalent daily dose ~ 40 mg in opioid-naïve patients) (Ref)
• Initiation of therapy or dose increase
• Rapid IV injection (ie, over <2 to 3 minutes)
• Opioid naïve (Ref)
• Opioid misuse (Ref)
• Acute overdose
• Concurrent administration of benzodiazepines, alcohol, or other CNS depressants
• Postoperative patients with comorbid cardiac or respiratory disease (Ref)
• Age >60 years (Ref)
• Males (Khanna 2020)
• Sleep disorder (eg, obstructive sleep apnea) (Ref)
• Chronic pulmonary disease
• Cachexia
• Debilitation
Abruptly stopping or reducing opioid use in patients with physical dependence on opioids can precipitate opioid-induced withdrawal (OIW) in adult and pediatric patients (Ref). Physical symptoms may include nausea, vomiting, diarrhea, abdominal cramps, tachycardia, chills, muscle aches, bone pain, agitation, anxiety, and insomnia. The presence and severity of withdrawal symptoms are associated with an increased risk of nonfatal overdose and receptive syringe sharing in people who inject drugs (Ref). Avoidance of withdrawal symptoms may drive continued opioid use (Ref). Symptoms typically dissipate over 4 to 7 days (Ref).
Mechanism: Withdrawal; opioids bind to mu-opioid receptors on neurons in the locus coeruleus (LC) of the brainstem, causing decreased norepinephrine (NE) release. Upon abrupt discontinuation, the absence of opioid stimulation causes LC hyperactivity, excessive NE release, and subsequent autonomic hyperactivity (Ref).
Onset: Rapid; symptoms typically occur within 12 hours of discontinuation and peak at 36 to 72 hours; varies based on half-life of opioid (Ref).
Risk factors:
• Higher cumulative dose (Ref)
• Prolonged exposure to opioids (Ref)
• Initiation of mixed agonist/antagonist or partial agonist analgesics (eg, buprenorphine, butorphanol, nalbuphine, pentazocine) (Ref) in patients currently or recently taking full mu-opioid agonists may cause precipitated opioid withdrawal. (Precipitated withdrawal is similar to OIW but with a faster onset.) (Ref)
• Opioid use disorder (Ref)
• Abrupt discontinuation or dose reduction (Ref)
• Concurrent use of benzodiazepines (Ref) or antipsychotics (Ref)
• Age <6 years, especially infants <6 months of age (Ref)
• Preexisting cognitive impairment (Ref)
• Critical illness involving the CNS (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Reported adverse reactions are for the extended-release formulation, unless otherwise noted.
1% to 10%:
Cardiovascular: Peripheral edema (2%)
Dermatologic: Pruritus (1%) (table 1)
|
Drug (Hydromorphone) |
Placebo |
Dosage Form |
Indication |
Number of Patients (Hydromorphone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
1% |
0% |
Extended-release tablets |
Moderate to severe low back pain |
134 |
134 |
Endocrine & metabolic: Weight loss (3%)
Gastrointestinal: Abdominal pain (3%), anorexia (≤1%), constipation (7%), decreased appetite (≤1%), nausea (9%), vomiting (6%), xerostomia (1%)
|
Drug (Hydromorphone) |
Placebo |
Dosage Form |
Indication |
Number of Patients (Hydromorphone) |
Number of Patients (Placebo) |
|---|---|---|---|---|---|
|
7% |
4% |
Extended-release tablets |
Moderate to severe low back pain |
134 |
134 |
Nervous system: Dizziness (2%), drowsiness (1%), insomnia (5%)
Neuromuscular & skeletal: Arthralgia (6%), muscle spasm (2%)
Frequency not defined (any formulation):
Cardiovascular: Bradycardia, chest pain, circulatory shock, extrasystoles, flushing, hypertension, hypotension, palpitations, presyncope, shock, syncope, tachycardia
Dermatologic: Diaphoresis, erythema of skin, hyperhidrosis, skin rash, urticaria
Endocrine & metabolic: Antidiuretic effect, decreased libido, decreased plasma testosterone, decreased serum potassium, dehydration, fluid retention, hyperuricemia
Gastrointestinal: Abdominal distention, abnormal stools, anal fissure, bezoar formation, biliary colic, delayed gastric emptying, diarrhea, diverticulitis of the gastrointestinal tract, duodenitis, dysgeusia, dyspepsia, dysphagia, eructation, flatulence, gastroenteritis, gastrointestinal motility disorder, hematochezia, hemorrhoids, increased appetite, increased serum amylase, intestinal obstruction, intestinal perforation, painful defecation
Genitourinary: Dysuria, hypogonadism, sexual disorder, urinary frequency, urinary hesitancy, urinary retention, urination disorder
Hematologic & oncologic: Bruise
Local: Injection-site reaction, pain at injection site, urticaria at injection site
Nervous system: Abnormal dreams, abnormal gait, aggressive behavior, agitation, anxiety, asthenia, ataxia, balance impairment, chills, cognitive dysfunction, decreased body temperature, depression, disorientation, disruption of body temperature regulation (sensation of), disturbance in attention, drug abuse, drug dependence, dysarthria, dysphoria, encephalopathy, euphoria, falling, hallucination, hangover effect, headache, hyperesthesia, hyperreflexia, hypoesthesia, impaired consciousness, increased intracranial pressure, intoxicated feeling, jitteriness, malaise, memory impairment, mood changes, neonatal withdrawal, nervousness, opioid withdrawal syndrome, panic attack, paranoid ideation, paresthesia, psychomotor agitation, restlessness, sedated state, suicidal ideation, tremor, vertigo
Neuromuscular & skeletal: Laryngospasm, muscle rigidity, myalgia
Ophthalmic: Blurred vision, diplopia, dry eye syndrome, miosis, nystagmus disorder, visual impairment
Otic: Tinnitus
Respiratory: Apnea, bronchospasm, hyperventilation, hypoxia, respiratory depression, respiratory distress, rhinorrhea, sneezing
Miscellaneous: Crying, fever
Postmarketing (any formulation):
Endocrine & metabolic: Hyperprolactinemia (Molitch 2008, Vuong 2010)
Genitourinary: Erectile dysfunction
Hepatic: Increased liver enzymes
Hypersensitivity: Anaphylaxis, hypersensitivity reaction
Nervous system: Confusion, fatigue, hyperalgesia, lethargy, myoclonus, seizure
Neuromuscular & skeletal: Dyskinesia
Respiratory: Dyspnea, oropharyngeal edema
US labeling: Hypersensitivity (eg, anaphylaxis) to hydromorphone, hydromorphone salts, or any component of the formulation; significant respiratory depression; acute or severe bronchial asthma in an unmonitored setting or in absence of resuscitative equipment or ventilatory support; gastrointestinal obstruction, including paralytic ileus (known or suspected).
Additional product-specific contraindications:
Dilaudid-HP injection: Opioid-nontolerant patients.
Hydromorphone ER tablets: Opioid-nontolerant patients; preexisting GI surgery and/or diseases resulting in narrowing of GI tract or blind loops in the GI tract.
Suppository: Hypersensitivity (eg, anaphylaxis) to sulfite-containing medications.
Canadian labeling: Hypersensitivity to hydromorphone or any component of the formulation.
Dilaudid, Hydromorph Contin: Known or suspected mechanical GI obstruction (eg, bowel obstruction or strictures) or any disease that affects bowel transit (eg, ileus of any type); suspected surgical abdomen (eg, acute appendicitis or pancreatitis); mild, intermittent, or short-duration pain that can be managed with other pain medications; acute respiratory depression, hypercarbia and cor pulmonale; acute alcoholism, delirium tremens, and convulsive disorders; severe CNS depression, increased cerebrospinal or intracranial pressure, and head injury; coadministration with monoamine oxidase inhibitors (concomitant use or within 14 days); women during pregnancy, labor and delivery, or breastfeeding.
Dilaudid HP: Patients not already receiving high doses or high concentrations of opioids.
Hydromorphone HP, Hydromorphone HP Forte, Hydromorphone 0.4 mg/mL injection: Patients not already receiving high doses or high concentrations of opioids; known or suspected mechanical gastrointestinal obstruction (eg, bowel obstruction or strictures) or any diseases/conditions that affect bowel transit (eg, ileus of any type); suspected surgical abdomen (eg, acute appendicitis or pancreatitis); mild pain that can be managed with other pain medications; acute or severe bronchial asthma, chronic obstructive airway, or status asthmaticus; acute respiratory depression, elevated carbon dioxide levels in the blood and cor pulmonale; acute alcoholism, delirium tremens, and convulsive disorders; severe CNS depression, increased cerebrospinal or intracranial pressure, and head injury; coadministration with monoamine oxidase inhibitors (concomitant use or within 14 days); women during pregnancy, labor and delivery, or breastfeeding.
Syrup: Respiratory depression in the absence of resuscitative equipment; status asthmaticus.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Additional product-specific contraindications:
Dilaudid: Hypersensitivity to other opioid analgesics; acute asthma or other obstructive airway and status asthmaticus.
Hydromorph Contin: Hypersensitivity to other opioid analgesics; acute asthma or severe bronchial asthma or status asthmaticus; management of acute pain, including use in outpatient or day surgeries; management of perioperative pain.
Hydromorphone HP, Hydromorphone HP Forte: Signs of intoxication, including due to centrally acting sedatives and/or stimulants, or in any other acute clinical condition that would increase risk of an adverse event when used for supervised injectable opioid agonist therapy.
Concerns related to adverse effects:
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving).
• Hypotension: May cause severe hypotension (including orthostatic hypotension and syncope); use with caution in patients with hypovolemia, cardiovascular disease (including acute myocardial infarction), or drugs that may exaggerate hypotensive effects (including phenothiazines or general anesthetics). Avoid use in patients with circulatory shock.
• 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.
• Phenanthrene hypersensitivity: Use with caution in patients with hypersensitivity reactions to other phenanthrene derivative opioid agonists (codeine, hydrocodone, levorphanol, oxycodone, oxymorphone).
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 with caution in patients with biliary tract dysfunction, including acute pancreatitis; opioids may cause constriction of 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.
• Delirium tremens: Use with caution in patients with delirium tremens.
• GI narrowing: Hydromorphone ER tablets are nondeformable; do not administer to patients with preexisting severe GI narrowing (eg, esophageal motility, small bowel inflammatory disease, short gut syndrome, history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, Meckel's diverticulum); obstruction may occur.
• 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 in patients with hepatic impairment; dosage reduction recommended in moderate to severe impairment. ER tablets are not recommended in severe impairment.
• Mental health conditions: Use opioids with caution for chronic pain in patients with mental health conditions (eg, depression, anxiety disorders, post-traumatic 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 in patients with renal impairment; dosage reduction recommended. ER tablets are not recommended in severe 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.
• Seizures: Use with caution in patients with a history of seizure disorders; may cause or exacerbate preexisting seizures.
• 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]).
• Thyroid dysfunction: Use with caution in patients with thyroid dysfunction.
Special populations:
• 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.
Dosage form specific issues:
• Extended-release tablets: Therapy should only be prescribed by health care professionals familiar with the use of potent opioids for chronic pain. Tablets may be visible on abdominal x-rays, especially when digital enhancing techniques are used. The tablet shell may appear in the excreted stool.
• Lactose: Some formulations may contain lactose.
• Latex: Vial stoppers of single-dose injectable vials may contain latex.
• Sodium metabisulfite: Some dosage forms may contain trace amounts of sodium metabisulfite, which may cause allergic reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in susceptible individuals.
Other warnings/precautions:
• Abuse/misuse/diversion: Use with caution in patients with a history of substance use 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 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]).
• IM administration: Variable absorption and a lag time to peak effect may result from IM use.
• IV administration: Administer IV very slowly; rapid IV injection of opioid analgesics increases the possibility of side effects such as hypotension and respiratory depression.
• Naloxone access: Discuss the availability of naloxone 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), or have experienced opioid-induced respiratory depression/opioid overdose. Additionally, health care providers should consider prescribing naloxone 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 (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, 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.
• REMS program: Additional information is available at www.opioidanalgesicrems.com or at 1-800-503-0784.
• Surgery: Use immediate-release formulations with caution in the perioperative setting; severe pain may antagonize the respiratory depressant effects of hydromorphone. Opioids decrease bowel motility; monitor for decreased bowel motility in postoperative patients receiving opioids. Use with caution in the perioperative setting; individualize treatment when transitioning from parenteral to oral analgesics.
Prolonged use of any hydromorphone product during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Liquid, Oral, as hydrochloride:
Dilaudid: 1 mg/mL (473 mL) [contains methylparaben, propylparaben, sodium metabisulfite]
Generic: 1 mg/mL (473 mL)
Solution, Injection, as hydrochloride:
Generic: 1 mg/mL (0.5 mL); 2 mg/mL (1 mL [DSC], 20 mL)
Solution, Injection, as hydrochloride [preservative free]:
Dilaudid: 0.2 mg/mL (1 mL); 1 mg/mL (0.5 mL, 1 mL); 2 mg/mL (1 mL)
Generic: 1 mg/mL (0.5 mL [DSC], 1 mL); 2 mg/mL (1 mL); 4 mg/mL (1 mL); 10 mg/mL (1 mL, 5 mL, 50 mL); 50 mg/5 mL (5 mL); 500 mg/50 mL (50 mL)
Suppository, Rectal, as hydrochloride:
Generic: 3 mg (6 ea)
Tablet, Oral, as hydrochloride:
Dilaudid: 2 mg, 4 mg [contains quinoline (d&c yellow #10) aluminum lake, sodium metabisulfite]
Dilaudid: 8 mg [contains sodium metabisulfite]
Generic: 2 mg, 4 mg, 8 mg
Tablet Extended Release 24 Hour, Oral, as hydrochloride:
Generic: 8 mg, 12 mg, 16 mg, 32 mg
Yes
Liquid (Dilaudid Oral)
1 mg/mL (per mL): $1.21
Liquid (HYDROmorphone HCl Oral)
1 mg/mL (per mL): $0.40 - $0.60
Solution (Dilaudid Injection)
0.2 mg/mL (per mL): $3.60
1 mg/mL (per 0.5 mL): $4.98
2 mg/mL (per mL): $4.98
Solution (HYDROmorphone HCl Injection)
1 mg/mL (per mL): $3.12 - $5.88
2 mg/mL (per mL): $2.30 - $7.88
4 mg/mL (per mL): $3.77
Solution (HYDROmorphone HCl PF Injection)
1 mg/mL (per mL): $5.18
2 mg/mL (per mL): $5.18
4 mg/mL (per mL): $5.38
10 mg/mL (per mL): $4.19 - $5.64
Suppository (HYDROmorphone HCl Rectal)
3 mg (per each): $12.27
Tablet, 24-hour (HYDROmorphone HCl ER Oral)
8 mg (per each): $7.73 - $9.24
12 mg (per each): $11.54 - $13.81
16 mg (per each): $15.41 - $18.41
32 mg (per each): $20.49 - $24.35
Tablets (Dilaudid Oral)
2 mg (per each): $2.79
4 mg (per each): $4.56
8 mg (per each): $8.30
Tablets (HYDROmorphone HCl Oral)
2 mg (per each): $0.11 - $0.48
4 mg (per each): $0.15 - $0.69
8 mg (per each): $0.61 - $1.38
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. [DSC] = Discontinued product
Capsule Extended Release 12 Hour, Oral:
Hydromorph Contin: 3 mg [contains quinoline yellow (d&c yellow #10)]
Hydromorph Contin: 4.5 mg [contains fd&c blue #1 (brilliant blue)]
Hydromorph Contin: 6 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10)]
Hydromorph Contin: 9 mg [contains fd&c blue #1 (brilliant blue)]
Hydromorph Contin: 12 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye), quinoline yellow (d&c yellow #10)]
Hydromorph Contin: 18 mg, 24 mg
Hydromorph Contin: 30 mg [contains fd&c blue #1 (brilliant blue), fd&c red #40 (allura red ac dye)]
Generic: 3 mg [DSC], 4.5 mg, 6 mg [DSC], 9 mg [DSC], 12 mg [DSC], 18 mg, 24 mg [DSC], 30 mg
Solution, Injection:
Generic: 20 mg/mL (50 mL); 50 mg/mL (1 mL, 50 mL); 100 mg/mL (10 mL)
Solution, Injection, as hydrochloride:
Generic: 1 mg/mL (1 mL); 2 mg/mL (1 mL, 2 mL); 10 mg/mL (1 mL, 5 mL, 10 mL, 50 mL)
Solution, Intravenous, as hydrochloride:
Generic: 20 mg/50 mL in NaCl 0.9% (50 mL); 40 mg/100 mL (100 mL)
Syrup, Oral:
Generic: 1 mg/mL (500 mL)
Tablet, Oral:
Dilaudid: 1 mg [contains fd&c blue #1 (brill blue) aluminum lake, quinoline yellow (d&c yellow #10)]
Generic: 1 mg
Tablet, Oral, as hydrochloride:
Dilaudid: 2 mg, 4 mg [contains quinoline yellow (d&c yellow #10)]
Dilaudid: 8 mg
Generic: 2 mg, 4 mg, 8 mg
C-II
Parenteral: Note: Vial stopper may contain latex.
Extreme caution should be taken to avoid confusing the highly concentrated injectable product (hydromorphone HP) containing 10 mg/mL with the standard parenteral formulations containing hydromorphone 1, 2, or 4 mg/mL. Hydromorphone HP is for use in opioid-tolerant patients only; confusion could result in overdose and death.
IM, SubQ: May be given SubQ or IM; however, IM administration is not recommended and should be avoided (Ref). IM administration is painful and may result in variable absorption, a lag time to peak effect, a rapid fall of action compared to oral administration, and may lead to nerve injury. SubQ administration is a more reliable and less painful alternative route of administration compared to IM (Ref).
IV: For IVP, must be given slowly over at least 2 to 3 minutes (rapid IVP has been associated with an increase in side effects, especially respiratory depression and hypotension). For other clinical situations (eg, sedation in the mechanically ventilated patient), a continuous infusion may also be administered, when appropriate (Ref).
Oral: Hydromorphone is available in an 8 mg immediate-release tablet and an 8 mg extended-release tablet. Extreme caution should be taken to avoid confusing dosage forms.
Hydromorphone ER: Tablets should be swallowed whole; do not crush, break, chew, dissolve, snort, or inject. Administer with or without food.
Bariatric surgery: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Switch to IR tablet or oral solution.
Hydromorph Contin [Canadian product]: For oral use only. Capsule should be swallowed whole; do not crush or chew. Contents may be sprinkled on a tablespoon of applesauce (stored at room temperature or under refrigeration) or custard (stored at room temperature) and swallowed without chewing as soon as possible (discard if not consumed within 30 minutes); patient should then rinse mouth with water to ensure entire contents are swallowed.
Oral solution: Ensure accuracy when prescribing, dispensing, and administering. Dosing errors due to confusion between mg and mL can result in accidental overdose and death. A calibrated oral syringe/dosing cup that can measure and deliver the prescribed dose accurately should be used; do not use a household teaspoon or tablespoon to measure dose.
Oral: Note: Hydromorphone is available in an 8 mg immediate-release tablet and an 8 mg extended-release tablet. Extreme caution should be taken to avoid confusing dosage forms.
Immediate release: Administer with food or milk to decrease GI upset.
Parenteral: Note: Vial stopper may contain latex.
Injectable formulation is available in multiple strengths. Extreme caution should be taken to avoid confusing the highly concentrated injectable product (hydromorphone HP) containing 10 mg/mL with the standard parenteral formulations containing hydromorphone ≤4 mg/mL. Hydromorphone HP is for use in opioid-tolerant patients only; confusion could result in overdose and death.
IV: Administer via slow IV injection over at least 2 to 3 minutes; rapid IV administration has been associated with an increase in side effects, especially respiratory depression and hypotension.
IM: May be administered IM, but not recommended due to variable absorption and a lag time to peak effect (Ref).
Rectal: Insert suppository rectally and retain
Note: Premixed solutions may be available.
Continuous IV infusion: 0.2 mg/mL, 1 mg/mL, 5 mg/mL in NS or D5W.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Dilaudid: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/019891s031,019892s041lbl.pdf#page=32.
Exalgo: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021217s025lbl.pdf#page=31. Medication guides are also available at http://www.exalgorems.com.
Hydromorphone hydrochloride extended-release tablets:https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/204278Orig1s000MG.pdf.
Pain management:
Immediate release:
Tablet, oral solution, injection, suppository: Management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
HP injection: Management of pain severe enough to require an opioid analgesic in opioid-tolerant patients who require higher doses of opioids and for which alternative treatments are inadequate.
Extended release: Management of pain in opioid-tolerant patients that is severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.
Limitations of use: Because of the risks of substance use disorder, abuse, and misuse with opioids, which may occur at any dosage or duration, reserve hydromorphone for use in patients for whom alternative treatment options (eg, nonopioid analgesics, opioid combination products) have not been tolerated or are not expected to be tolerated; have not provided adequate analgesia or are not expected to provide adequate analgesia. IR formulations are not intended to be used for an extended period of time unless the pain remains severe enough to require an opioid analgesic and for which alternative treatment options continue to be inadequate. ER formulations are not indicated as as-needed analgesics.
Critically ill patients in the ICU, analgesia and sedation
Dilaudid may be confused with Demerol, Dilantin
HYDROmorphone may be confused with buprenorphine, diamorphine, hydrALAZINE, hydrOXYzine, morphine, oxyMORphone
HYDROmorphone may be confused with morphine; significant overdoses have occurred when hydromorphone products have been inadvertently administered instead of morphine sulfate. Commercially available prefilled syringes of both products looks similar and are often stored in close proximity to each other. Note: Hydromorphone 1 mg oral is approximately equal to morphine 4 mg oral; hydromorphone 1 mg IV is approximately equal to morphine 5 mg IV
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drug classes which have a heightened risk of causing significant patient harm when used in error.
Dilaudid, Dilaudid-HP: Extreme caution should be taken to avoid confusing the highly-concentrated (Dilaudid-HP) injection with the less-concentrated (Dilaudid) injectable product.
Extended-release tablets: Extreme caution should be taken to avoid confusing the extended-release hydromorphone 8 mg tablets with immediate-release hydromorphone 8 mg tablets.
Significant differences exist between oral and IV dosing. Use caution when converting from one route of administration to another.
None known.
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 Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Alvimopan: Opioid Agonists may enhance the adverse/toxic effect 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
Amphetamines: May enhance the analgesic effect of Opioid Agonists. Risk C: Monitor therapy
Anticholinergic Agents: May enhance the adverse/toxic effect of Opioid Agonists. Specifically, the risk for constipation and urinary retention may be increased with this combination. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect 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
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect 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 enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
CNS Depressants: May enhance the CNS depressant effect 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
Daridorexant: May enhance the CNS depressant effect 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 enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
DexmedeTOMIDine: CNS Depressants may enhance the CNS depressant effect 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
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Diuretics: Opioid Agonists may enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy
DroPERidol: May enhance the CNS depressant effect 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
Eluxadoline: Opioid Agonists may enhance the constipating effect of Eluxadoline. Risk X: Avoid combination
Flunarizine: CNS Depressants may enhance the CNS depressant effect of Flunarizine. Risk X: Avoid combination
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect 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
Gastrointestinal Agents (Prokinetic): Opioid Agonists may diminish the therapeutic effect of Gastrointestinal Agents (Prokinetic). Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect 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
Ixabepilone: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect 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
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect 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
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of HYDROmorphone. Management: Coadministration of hydromorphone and monoamine oxidase (MAO) inhibitors (or within 14 days of stopping an MAO inhibitor) is not recommended. If required, use test doses, titrate small doses frequently, and monitor for CNS and respitatory depression. Risk D: Consider therapy modification
Nabilone: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Nalfurafine: Opioid Agonists may enhance the adverse/toxic effect of Nalfurafine. Opioid Agonists may diminish the therapeutic effect of Nalfurafine. Risk C: Monitor therapy
Nalmefene: May diminish the therapeutic effect 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 diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid combination
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect 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 diminish the analgesic effect 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 combination
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect 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 enhance the CNS depressant effect 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 enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Pegvisomant: Opioid Agonists may diminish the therapeutic effect of Pegvisomant. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Procarbazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Ramosetron: Opioid Agonists may enhance the constipating effect of Ramosetron. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect 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 enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Samidorphan: May diminish the therapeutic effect of Opioid Agonists. Risk X: Avoid combination
Serotonergic Agents (High Risk): Opioid Agonists may enhance the serotonergic effect 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 therapy
Sincalide: Drugs that Affect Gallbladder Function may diminish the therapeutic effect 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
Somatostatin Analogs: Opioid Agonists may diminish the analgesic effect of Somatostatin Analogs. Opioid Agonists may enhance the analgesic effect of Somatostatin Analogs. Risk C: Monitor therapy
Succinylcholine: May enhance the bradycardic effect of Opioid Agonists. Risk C: Monitor therapy
Suvorexant: CNS Depressants may enhance the CNS depressant effect 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
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect 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 enhance the CNS depressant effect 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]).
Hydromorphone crosses the placenta (Alexander 2018; Puhto 2020).
Maternal use of opioids may be associated with poor fetal growth, stillbirth, and preterm delivery (CDC [Dowell 2022]). 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 can be used to treat acute pain associated with delivery when needed. Agents such as hydromorphone are generally reserved for patients with inadequate pain control following a reasonable trial with preferred therapy (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]).
Hydromorphone is present in breast milk (Edwards 2003).
The half-life of hydromorphone was 10.5 ± 5.2 hours in breast milk following a single intranasal dose of hydromorphone 2 mg (Edwards 2003).
Progressive lethargy requiring treatment with naloxone was noted in a 6-day old infant exposed to hydromorphone via breast milk (Schultz 2019).
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Nonopioid analgesics are preferred for lactating patients who require pain control peripartum or for surgery outside of the postpartum period. When opioids are needed for lactating patients, use the lowest effective dose for the shortest duration of time to limit adverse events in the mother and breastfeeding infant. Limited use of hydromorphone may be considered. Analgesics delivered by patient-controlled analgesia or via the epidural route help limit infant exposure (AAP [Sachs 2013]; ABM [Martin 2018]; ABM [Reece-Stremtan 2017]; WHO 2002).
When chronic opioids are prescribed prenatally and continued postpartum, breastfeeding may be initiated to help mitigate potential newborn withdrawal; monitor both the mother and the infant (AAP [Meek 2022]; AAP [Patrick 2020]).
Monitor infants exposed to opioids via breast milk for drowsiness, sedation, feeding difficulties, or limpness (ACOG 2019). Withdrawal symptoms may occur when maternal use is discontinued, or breastfeeding is stopped.
Pain relief, respiratory and mental status, blood pressure; bowel function; signs/symptoms of misuse, abuse, and substance use disorder; signs or symptoms of hypogonadism or hypoadrenalism (Brennan 2013); signs or symptoms of hyperalgesia, including increased levels of pain upon opioid dosage increase, decreased levels of pain upon opioid dosage decrease, or pain from ordinarily nonpainful stimuli if there is no evidence of underlying disease progression, opioid tolerance, opioid withdrawal, or addictive behavior.
Alternate recommendations: Subacute or chronic pain (long-term therapy outside of end-of-life or palliative care, active cancer treatment, sickle cell disease, or medication-based opioid use disorder treatment): Evaluate benefits/risks of opioid therapy within 1 to 4 weeks of treatment initiation and with dose increases. In patients with subacute pain initially treated for acute pain, reassess pain and function after 30 days to address potentially reversible causes of pain and prevent unintentional long-term opioid therapy. In patients on long-term therapy, re-evaluate benefits/risks every 3 months during therapy or more frequently in patients at increased risk of overdose or opioid use disorder. Toxicology testing is recommended prior to initiation and at least yearly (includes controlled prescription medications, illicit drugs of abuse, and benzodiazepines). State prescription drug monitoring program (PDMP) data should be reviewed by clinicians prior to initiation and periodically during therapy (frequency ranging from every prescription to every 3 months) (CDC [Dowell 2022]).
Critically ill: The Numeric Rating Scale should be used in patients who are able to self-report pain. In patients who are unable to self-report pain, the Behavioral Pain Scale and the Critical-Care Pain Observational Tool can be used in intubated or nonintubated patients (SCCM [Devlin 2018]).
Binds to opioid receptors in the CNS, causing inhibition of ascending pain pathways, altering the perception of and response to pain; causes cough suppression by direct central action in the medulla; produces generalized CNS depression
Onset of action: Analgesic:
Immediate-release formulations:
Oral: 15 to 30 minutes; Peak effect: 30 to 60 minutes.
IV: 5 minutes; Peak effect: 10 to 20 minutes.
Extended-release tablet: 6 hours; Peak effect: ~9 hours (Angst 2001).
Duration:
Immediate-release formulations: Oral, IV: 3 to 4 hours; suppository may provide longer duration of effect.
Extended-release tablet: Duration of analgesia highly variable; may be sustained for ≥24 hours (Angst 2001).
Absorption: Oral: Rapidly absorbed; extensive first-pass effect; Extended-release tablet: Delayed; IM: Variable and delayed.
Distribution: Vd: 4 L/kg.
Protein binding: ~8% to 19%.
Metabolism: Hepatic via glucuronidation; to inactive metabolites; 85% to >95% is metabolized to hydromorphone-3-glucuronide; minor amounts as 6-hydroxy reduction metabolites (Cone 1997).
Bioavailability: Oral, immediate release: ~24%.
Half-life elimination:
Immediate-release formulations: 2 to 3 hours.
Extended-release tablets: Apparent half-life: ~11 hours (range: 8 to 15 hours).
Time to peak, plasma:
Immediate-release tablet: ≤1 hour.
Extended-release tablet: 12 to 16 hours.
Extended-release capsule [Canadian product]: ~5 hours.
Excretion: Urine (primarily as glucuronide conjugates); minimal unchanged drug is excreted in urine (~7%) and feces (1%).
Altered kidney function:
Immediate release: Cmax and AUC0-48 are increased 2-fold in patients with moderate (CrCl 40 to 60 mL/minute) and 3-fold in patients with severe (CrCl <30 mL/minute) renal impairment.
Hepatic function impairment: Cmax and AUC is increased 4-fold in patients with moderate (Child-Pugh class B) hepatic impairment.
Older adult: Extended release: Average 11% AUC increase in the elderly.
Sex:
Extended release: Women appear to have ~10% higher mean systemic exposure.
Immediate release: Women appear to have a 25% higher Cmax than men.
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