Introduction ⬇
VA Class:CN101
AHFS Class:
Generic Name(s):
Associated Monographs
Notification REMS: FDA approved a REMS for oxycodone to ensure that the benefits outweigh the risk. The REMS may apply to one or more preparations of oxycodone and consists of the following: medication guide and elements to assure safe use. See the FDA REMS page ([Web]). - FDA drug safety communication (4/13/2023):500 As part of its ongoing efforts to address the nation's opioid crisis, FDA is requiring several updates to the prescribing information of opioid pain medicines. The changes are being made to provide additional guidance for safe use of these drugs while also recognizing the important benefits when used appropriately. The changes apply to both immediate-release (IR) and extended-release/long-acting preparations (ER/LA).
- Updates to the IR opioids state that these drugs should not be used for an extended period unless the pain remains severe enough to require an opioid pain medicine and alternative treatment options are insufficient, and that many acute pain conditions treated in the outpatient setting require no more than a few days of an opioid pain medicine.
- Updates to the ER/LA opioids recommend that these drugs be reserved for severe and persistent pain requiring an extended period of treatment with a daily opioid pain medicine and for which alternative treatment options are inadequate.
- A new warning is being added about opioid-induced hyperalgesia (OIH) for both IR and ER/LA opioid pain medicines. This includes information describing the symptoms that differentiate OIH from opioid tolerance and withdrawal.
- Information in the boxed warning for all IR and ER/LA opioid pain medicines will be updated and reordered to elevate the importance of warnings concerning life-threatening respiratory depression, and risks associated with using opioid pain medicines in conjunction with benzodiazepines or other medicines that depress the central nervous system (CNS).
- Other changes will also be required in various other sections of the prescribing information to educate clinicians, patients, and caregivers about the risks of these drugs.
|
Oxycodone is a synthetic phenanthrene-derivative opiate agonist.
Uses ⬆ ⬇
Pain 
Conventional preparations of oxycodone hydrochloride are used orally for the management of moderate to severe acute or chronic pain when use of an opiate analgesic is appropriate.299,302,303
Oxycodone hydrochloride extended-release tablets and oxycodone myristate extended-release capsules are used orally for the relief of pain that is severe enough to require long-term, daily, around-the-clock use of an opiate analgesic.290,291 Because of the risks of addiction, abuse, and misuse associated with opiates even at recommended dosages, and because of the greater risks of overdose and death associated with extended-release opiate formulations, these extended-release preparations of oxycodone hydrochloride or oxycodone myristate should be reserved for use in patients for whom alternative treatment options (e.g., nonopiate analgesics, immediate-release opiates) are inadequate or not tolerated.290,291 Oxycodone hydrochloride extended-release tablets may be used for the relief of such pain in pediatric patients 11 years of age or older who are opiate tolerant and already receiving and tolerating opiate agonist therapy at a dosage equivalent to 20 mg or more of oxycodone hydrochloride daily.290 The manufacturer states that safety and efficacy of oxycodone myristate extended-release capsules have not been established in patients younger than 18 years of age.291 Oxycodone hydrochloride extended-release tablets and oxycodone myristate extended-release capsules are not intended for use on an as-needed (“prn”) basis.290,291
Extended-release tablets containing oxycodone hydrochloride in fixed combination with acetaminophen are used for the relief of acute pain that is severe enough to require opiate therapy and for which alternative treatments (e.g., nonopiate analgesics) are inadequate or not tolerated.305
For further information on the role of opiate analgesics in the management of acute or chronic pain, see Uses: Pain, in the Opiate Agonists General Statement 28:08.08.
Misuse and Abuse
Oxycodone has emerged as one of the most problematic abused opiate agonists in the US; therefore, patients should be advised about the risk of theft, and clinicians should be informed about abuse and diversion issues. (See Cautions.)
Dosage and Administration ⬆ ⬇
Administration
Oxycodone is administered orally as the hydrochloride salt, often in combination with nonopiate analgesics (e.g., acetaminophen), or as the myristate salt.
Conventional Oxycodone Hydrochloride Formulations
Some manufacturers state that their formulations of oxycodone hydrochloride conventional tablets should not be crushed and dissolved.302 These formulations should not be administered via gastric, nasogastric, or other feeding tube since they can obstruct the tube.302 Instead, these tablets should be administered intact with sufficient water to ensure that each tablet is completely swallowed immediately after it is placed in the mouth.302 The respective manufacturer's labeling should be consulted for specific recommendations.
Oxycodone hydrochloride is commercially available as a 5-mg/5-mL oral solution and as a 100-mg/5-mL oral concentrate solution; confusion between the different concentrations or between mg and mL can result in accidental overdosage and/or death.299,304 The oral concentrate solution should be used only in opiate-tolerant patients.304 Caution is required when prescribing, dispensing, and administering oral solutions of the drug to avoid dosing errors.299,304 Care should be taken to ensure that the appropriate dose is communicated and dispensed.299,304 Prescriptions should specify the intended total dose of the drug (in mg) along with the corresponding total volume (in mL).299,304 The calibrated measuring device provided with the particular formulation should always be used to ensure that the dose is measured and administered accurately.299,304
Oxycodone Hydrochloride and Acetaminophen Fixed-combination Extended-release Tablets
Extended-release tablets containing oxycodone hydrochloride in fixed combination with acetaminophen should be swallowed whole and should not be broken, chewed, crushed, cut, or dissolved, since such physical alteration of the tablets could result in rapid release of the drug and absorption of a potentially toxic dose.305 The fixed-combination extended-release tablets should be administered one at a time with enough water to ensure that each tablet is completely swallowed immediately after it is placed in the mouth; extended-release tablets should not be wet (e.g., soaked, licked) before they are placed in the mouth for swallowing.305 The tablets may be administered without regard to food.305 This formulation should not be used for administration through a nasogastric, gastric, or other feeding tube.305
Oxycodone Hydrochloride Extended-release Tablets
Oxycodone hydrochloride extended-release tablets should be swallowed whole and should not be broken, chewed, crushed, cut, split, or dissolved, since such physical alteration of the tablets could result in rapid release of the drug and absorption of a potentially toxic dose.290 Extended-release tablets should be administered one at a time with enough water to ensure that each tablet is completely swallowed immediately after it is placed in the mouth; extended-release tablets should not be wet (e.g., soaked, licked) before they are placed in the mouth for swallowing.290 Oxycodone hydrochloride extended-release tablets should not be administered rectally because of increased bioavailability and peak plasma concentrations compared with oral administration.300 (See Pharmacokinetics.) Food does not substantially affect the extent of oral absorption of oxycodone hydrochloride extended-release tablets.
Oxycodone Myristate Extended-release Capsules
Oxycodone myristate extended-release capsules must be administered orally with food.291 Each dose should be administered with approximately the same amount of food (whether given as an intact capsule or as capsule contents sprinkled on food or directly in the mouth) in order to ensure that consistent plasma concentrations of the drug are achieved.291 (See Pharmacokinetics.) For patients who have difficulty swallowing, the capsules may be opened and the contents sprinkled onto a small amount of soft food (e.g., applesauce, pudding, yogurt, ice cream, jam) or into a cup and then administered directly into the mouth.291 The capsule contents should be swallowed immediately, and the mouth should be rinsed to ensure that the entire dose has been swallowed.291
Alternatively, the capsule contents may be administered through a nasogastric or gastrostomy tube.291 The tube should first be flushed with water and then the capsule should be opened and the contents carefully poured directly into the tube; the capsule contents should not be premixed with the liquid that will be used to flush the tube.291 Following administration, the tube should be flushed with 15 mL of liquid (water, milk, or liquid nutritional supplement) and then flushed 2 more times, each time with 10 mL of liquid, to ensure that the entire dose is delivered.291
Dosage
Dosage of oxycodone hydrochloride is expressed in terms of the salt;290,299,302,303 dosage of oxycodone myristate is expressed in terms of oxycodone base.291
Oxycodone should be given at the lowest effective dosage and for the shortest duration of therapy consistent with the treatment goals of the patient.411,413,431,432,435 Reduced dosage is indicated in debilitated patients and in very young or very old patients. If concomitant therapy with other CNS depressants is required, the lowest effective dosages and shortest possible duration of concomitant therapy should be used.700,703 Some manufacturers recommend that initial dosages of 33-50% of the usual dosage be employed when therapy with oxycodone hydrochloride extended-release tablets is initiated in patients receiving other CNS depressants.290 When therapy with extended-release tablets containing oxycodone hydrochloride in fixed combination with acetaminophen is initiated in patients receiving other CNS depressants, the manufacturer states that the initial oxycodone hydrochloride dosage should be reduced by 50% (i.e., to 7.5 mg twice daily).305
For acute pain not related to trauma or surgery, the prescribed quantity should be limited to the amount needed for the expected duration of pain severe enough to require opiate analgesia (generally 3 days or less and rarely more than 7 days).411,433,434,435 When opiate analgesics are used for the management of chronic noncancer pain, the US Centers for Disease Control and Prevention (CDC) recommends that primary care clinicians carefully reassess individual benefits and risks before prescribing dosages equivalent to 50 mg or more of morphine sulfate daily (approximately 33 mg or more of oxycodone hydrochloride daily) and avoid dosages equivalent to 90 mg or more of morphine sulfate daily (approximately 60 mg or more of oxycodone hydrochloride daily) or carefully justify their decision to titrate the dosage to such levels.411 Other experts recommend consulting a pain management specialist before exceeding a dosage equivalent to 80-120 mg of morphine sulfate daily.423,431
Patients receiving long-term, daily, around-the-clock opiate analgesia should be reevaluated continually for adequacy of pain control and for adverse effects, as well as for manifestations of opiate withdrawal and for the development of addiction, abuse, or misuse.290,291,303 To reduce the risk of respiratory depression, appropriate dosage selection and titration are essential.290,291 The initial dosage of oxycodone must be individualized, taking into account the patient's severity of pain, response, prior analgesic use, and risk factors for addiction, abuse, and misuse.290,291,303 Because there is substantial interpatient variability in the relative potency of opiate analgesics and analgesic formulations, it is preferable to underestimate the patient's 24-hour opiate requirements and provide “rescue” therapy with an immediate-release opiate analgesic than to overestimate the requirements and manage an adverse reaction.290,291 Patients should be monitored closely for respiratory depression, especially during the first 24-72 hours of therapy and following any increase in dosage.290,291,303
In patients requiring long-term around-the-clock opiate analgesia, dosage of oxycodone should be titrated to a level that provides adequate analgesia and minimizes adverse effects.290,291,303 Frequent communication among the prescriber, other members of the healthcare team, the patient, and the patient's caregiver or family is important during periods of changing analgesic requirements, including the initial dosage titration period.290,291,303 Patients who experience breakthrough pain may require dosage adjustment or supplemental analgesia (i.e., “rescue” therapy with an immediate-release analgesic).290,291 If the level of pain increases after dosage stabilization, an attempt should be made to identify the source of increased pain before increasing the oxycodone dosage.290,291,303 During long-term therapy, the continued need for opiate analgesics should be continually reevaluated.290,291 If discontinuance of opiate therapy is required, the dosage should be tapered gradually to avoid manifestations of abrupt withdrawal.290,291,303
For further information on the management of opiate analgesic therapy, see Dosage and Administration: Dosage, in the Opiate Agonists General Statement 28:08.08.
Conventional (Immediate-release) Preparations
For the management of moderate to severe pain in patients who have not been receiving opiate analgesic therapy, the usual initial adult dosage of conventional oxycodone hydrochloride preparations is 5-15 mg every 4-6 hours as needed.299,302 Although safety and efficacy of conventional oxycodone hydrochloride preparations have not been established in children,299,302 the drug has been recommended for use in pediatric patients.296,298 For the management of moderate to severe pain in children, some experts have suggested a dosage of 0.05-0.15 mg/kg (up to 5 mg) every 4-6 hours as needed.296,297,298
Dosage should be adjusted based on the response and tolerance of the patient.299,302 Patients with chronic pain may require around-the-clock rather than as-needed dosing.302 Because opiate analgesics given on a fixed dosage schedule have a narrow therapeutic index in certain patient populations, especially when used concomitantly with other drugs, fixed dosage schedules should be reserved for patients for whom the benefits of opiate analgesia outweigh the risks of respiratory depression, altered mental state, and orthostatic hypotension.302 In patients switching from other opiates or opiate formulations to therapy with conventional oxycodone hydrochloride preparations, the potency of the prior opiate relative to that of oxycodone should be considered, keeping in mind that published dosage conversion ratios are only approximations.299,302 Conservative initial dosages, patient monitoring, and dosage adjustment based on response are essential when the opiate or opiate formulation is switched.299,302
When opiate analgesics are administered in fixed combination with nonopiate analgesics, the opiate dosage may be limited by the nonopiate component.117,119,120,121 Because commercially available preparations contain oxycodone and nonopiate analgesics in various fixed ratios and because these nonopiate analgesics also are available in many other prescription and OTC preparations, care should be taken to ensure that therapy is not duplicated and that dosage of the nonopiate drug does not exceed maximum recommended dosages.117,118,119,121
When therapy with conventional preparations of oxycodone hydrochloride is discontinued following long-term opiate therapy, dosage generally can be reduced by 25-50% per day.299,302 If symptoms of withdrawal occur, the dosage should be increased to the prior level and tapered more slowly.299,302
Oxycodone Hydrochloride and Acetaminophen Fixed-combination Extended-release Tablets
When extended-release tablets containing oxycodone hydrochloride in fixed combination with acetaminophen are used for the management of acute pain in adults, the recommended oxycodone hydrochloride dosage is 15 mg (given in fixed combination with 650 mg of acetaminophen) every 12 hours.305 The second dose may be administered as soon as 8 hours after the initial dose if required for adequate analgesia, but all subsequent doses should be administered at 12-hour intervals.305 When therapy with this formulation is discontinued in a patient who may be opiate dependent, the dosage should be tapered gradually (i.e., reduced by 50% every 2-4 days) to avoid manifestations of abrupt withdrawal.305
When opiate analgesics are administered in fixed combination with acetaminophen, the opiate dosage may be limited by the acetaminophen component.117,119,120,121 Because acetaminophen also is available in many other prescription and OTC preparations, care should be taken to ensure that therapy is not duplicated and that dosage of acetaminophen does not exceed maximum recommended dosages.117,118,119,121
Oxycodone Hydrochloride Extended-release Tablets
Adult Dosage
For the management of pain severe enough to require daily, around-the-clock, long-term opiate analgesia in adults who are not opiate tolerant, therapy with oxycodone hydrochloride extended-release tablets should be initiated at a dosage of 10 mg every 12 hours.290 The manufacturers state that use of higher initial dosages in patients who are not opiate tolerant may result in fatal respiratory depression.290 A single dose exceeding 40 mg, total daily dosages exceeding 80 mg, and 60- and 80-mg extended-release tablets should be used only in adults in whom tolerance to an opiate of comparable potency has been established.290 Adults are considered opiate tolerant if they have been receiving opiate therapy consisting of at least 60 mg of morphine sulfate daily, 25 mcg of transdermal fentanyl per hour, 30 mg of oral oxycodone hydrochloride daily, 8 mg of oral hydromorphone hydrochloride daily, 25 mg of oxymorphone hydrochloride daily, or an equianalgesic dosage of another opiate daily for at least 1 week.290
In patients who are being switched from other opiates to oxycodone hydrochloride extended-release tablets, all other around-the-clock opiate analgesics should be discontinued when therapy with the extended-release tablets is initiated.290 For patients receiving conventional oxycodone preparations, the total daily dosage of the drug should be calculated and given as oxycodone hydrochloride extended-release tablets in 2 divided doses at 12-hour intervals.290
For patients receiving conventional formulations of other opiates, the recommended initial dosage of oxycodone hydrochloride extended-release tablets is 10 mg every 12 hours, since dosage conversion factors have not been established in clinical trials.290 Particularly close monitoring is required when patients are switched from methadone, since conversion ratios between methadone and other opiates vary widely depending on extent of prior methadone exposure and because methadone has a long half-life and tends to accumulate in plasma.290
Patients receiving fentanyl transdermal systems may receive oxycodone hydrochloride extended-release tablets beginning 18 hours after removal of the transdermal system.290 The manufacturers state that an initial oxycodone hydrochloride dosage of approximately 10 mg every 12 hours as extended-release tablets can be substituted for each 25-mcg/hour increment in fentanyl transdermal system dosa however, patients should be monitored closely, since clinical experience with this dosage conversion ratio is limited.290
Dosage adjustments in adults generally may be made in increments of 25-50% of the total daily dosage at intervals of 1-2 days, to a level that provides adequate analgesia and minimizes adverse effects.290 Safety and efficacy of dosing intervals shorter than 12 hours have not been established.290
The manufacturer states that usual doses and dosing intervals for oxycodone hydrochloride extended-release tablets may be appropriate for geriatric patients, since no unexpected adverse effects were observed in geriatric patients receiving this preparation in clinical trials with appropriate initiation of therapy and dosage titration.290 However, the manufacturer recommends that initial dosages of 33-50% of the usual dosage be employed when therapy with oxycodone hydrochloride extended-release tablets is initiated in non-opiate-tolerant, debilitated geriatric patients.290 Dosage in geriatric patients should be titrated cautiously.290
Pediatric Dosage
Extended-release oxycodone hydrochloride tablets should be used only in opiate-tolerant pediatric patients 11 years of age and older; such patients must be receiving and tolerating opiate analgesics for at least 5 consecutive days, and at a dosage of at least 20 mg of oxycodone hydrochloride (or equivalent) daily for at least 2 days immediately prior to initiation of therapy with oxycodone hydrochloride extended-release tablets.290 All other around-the-clock opiate analgesics should be discontinued when therapy with the extended-release tablets is initiated.290
In pediatric patients who are being switched from other opiate therapy to oxycodone hydrochloride extended-release tablets, the manufacturer states that the conversion factors in Table 1 may be used as a guide for selecting an initial dosage of the extended-release tablets.290 The manufacturer cautions that the doses in Table 1 are not equianalgesic doses and the table cannot be used to switch patients from oxycodone hydrochloride extended-release tablets to another opiate, as this will result in overestimation of the dosage of the new opiate and possible fatal overdosage.290 For patients receiving a single opiate analgesic, the current total daily dosage of the opiate should be multiplied by the appropriate conversion factor in Table 1 to calculate the approximate daily dosage of oxycodone hydrochloride extended-release tablets; the calculated daily dosage should then be divided in half for administration every 12 hours.290 For patients receiving more than one opiate analgesic, the approximate daily dosage of extended-release oxycodone hydrochloride should be calculated for each opiate and then those totals should be summed to obtain the approximate total daily dosage of oxycodone hydrochloride extended-release tablets; the calculated total daily dosage should then be divided in half for administration every 12 hours.290 For patients receiving analgesics containing opiates and nonopiates in a fixed ratio, only the opiate component should be considered in the conversion.290 Calculated doses that do not correspond to an available tablet strength should always be rounded down to the nearest whole tablet when initiating therapy; if the calculated total daily dosage is less than 20 mg, patients should not be switched to the extended-release formulation.290
Dosage adjustments in pediatric patients may be made in increments of 25% of the total daily dosage at intervals of 1-2 days, to a level that provides adequate analgesia and minimizes adverse effects.290 Safety and efficacy of dosing intervals shorter than 12 hours have not been established.290
In patients receiving asymmetric dosing, the higher dose should be taken in the morning and the lower dose in the evening.290
Table 1. Conversion Factors When Switching Pediatric Patients 11 Years of Age or Older to Oxycodone Hydrochloride Extended-release Tablets290
| Conversion Factor |
|---|
Prior Opiate | Oral | Parenterala |
|---|
Oxycodone | 1 | |
Hydrocodone | 0.9 | - |
Hydromorphone | 4 | 20 |
Morphine | 0.5 | 3 |
Tramadol | 0.17 | 0.2 |
aFor patients receiving high-dose parenteral opiates, a more conservative conversion is warranted (e.g., for high-dose parenteral morphine, use 1.5 instead of 3 as a multiplication factor).
Pediatric patients receiving fentanyl transdermal systems may receive oxycodone hydrochloride extended-release tablets beginning 18 hours after removal of the transdermal system.290 The manufacturers state that an initial oxycodone hydrochloride dosage of approximately 10 mg every 12 hours as extended-release tablets can be substituted for each 25-mcg/hour increment in fentanyl transdermal system dosa however, patients should be monitored closely, since clinical experience with this dosage conversion ratio is limited.290
Oxycodone Myristate Extended-release Capsules
Adult Dosage
For the management of pain that is severe enough to require long-term, daily, around-the-clock analgesia in adults who are not currently receiving opiate analgesics or are not opiate tolerant, therapy with oxycodone myristate extended-release capsules should be initiated at a dosage of 9 mg of oxycodone (equivalent to 10 mg of oxycodone hydrochloride) every 12 hours.291 Use of higher initial dosages in patients who are not opiate tolerant may result in fatal respiratory depression.291 A single dose exceeding 36 mg of oxycodone (equivalent to 40 mg of oxycodone hydrochloride) or total daily dosages exceeding 72 mg of oxycodone (equivalent to 80 mg of oxycodone hydrochloride) should be used only in patients in whom tolerance to an opiate of comparable potency has been established.291 Patients are considered opiate tolerant if they have been receiving at least 60 mg of oral morphine sulfate daily, 25 mcg of transdermal fentanyl per hour, 30 mg of oral oxycodone hydrochloride daily, 8 mg of oral hydromorphone hydrochloride daily, 25 mg of oral oxymorphone hydrochloride daily, 60 mg of oral hydrocodone bitartrate daily, or an equianalgesic dose of another opiate daily for at least 1 week.291
In adults who are being transferred from other oral opiates to therapy with oxycodone myristate extended-release capsules, all other around-the-clock opiate analgesics should be discontinued when therapy with the extended-release capsules is initiated.291 Dosage must be carefully individualized since overestimation of the initial dosage in opiate-tolerant patients can result in fatal overdosage.291 For adults receiving other oral oxycodone preparations, the total daily dosage of the drug should be calculated and given as oxycodone myristate extended-release capsules in 2 divided doses at 12-hour intervals; because oxycodone myristate extended-release capsules are not bioequivalent to other extended-release preparations of the drug, dosage adjustment may be necessary.291 For patients receiving other opiate analgesics, the recommended initial dosage of oxycodone myristate extended-release capsules is 9 mg of oxycodone every 12 hours, since dosage conversion factors have not been established in clinical trials.291 Particularly close monitoring is required when patients are switched from methadone, since conversion ratios between methadone and other opiates vary widely depending on extent of prior methadone exposure and because methadone has a long half-life and tends to accumulate in plasma.291
Adults receiving therapy with fentanyl transdermal system may receive oxycodone myristate extended-release capsules beginning 18 hours after removal of the transdermal system.291 The manufacturer states that a conservative initial oxycodone dosage of approximately 9 mg every 12 hours as extended-release capsules can be substituted for each 25-mcg/hour increment in transdermal fentanyl system dosa however, patients should be monitored closely, since clinical experience with this dosage conversion ratio is limited.291
Dosage adjustments generally may be made in increments of 25-50% of the total daily dosage at intervals of 1-2 days, to a level that provides adequate analgesia and minimizes adverse effects.291 Safety and efficacy of dosing intervals shorter than 12 hours have not been established.291 The maximum recommended dosage of oxycodone myristate extended-release capsules is 288 mg of oxycodone daily (eight 36-mg capsules), since safety of excipients in the formulation at dosages exceeding 288 mg daily has not been established.291
The manufacturer states that usual doses and dosing intervals for oxycodone myristate extended-release capsules may be appropriate for geriatric patients, since no unexpected adverse effects were observed in geriatric patients receiving this preparation in a clinical trial with appropriate initiation of therapy and dosage titration.291 Nevertheless, dosage should be selected with caution because of the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in geriatric patients and titrated slowly because of the risk of respiratory depression.291
Dosage in Renal and Hepatic Impairment
In patients with impaired hepatic function, initial oxycodone dosages should be conservative and adjusted according to the clinical situation.290,291,299,302 The manufacturers recommend that therapy with oxycodone hydrochloride extended-release tablets or oxycodone myristate extended-release capsules be initiated at 33-50% of the usual dosage and titrated carefully.290,291 When extended-release tablets containing oxycodone hydrochloride in fixed combination with acetaminophen are used for the management of acute pain in patients with hepatic impairment, the manufacturer recommends an initial oxycodone hydrochloride dose of 7.5 mg (given in fixed combination with 325 mg of acetaminophen); dosage should be adjusted as needed with close monitoring for respiratory depression.305
In patients with impaired renal function (creatinine clearance less than 60 mL/minute), initial oxycodone dosages should be conservative and adjusted according to the clinical situation.290,291,299,302 When extended-release tablets containing oxycodone hydrochloride in fixed combination with acetaminophen are used for the management of acute pain in patients with renal impairment, the manufacturer recommends an initial oxycodone hydrochloride dose of 7.5 mg (given in fixed combination with 325 mg of acetaminophen); dosage should be adjusted as needed with close monitoring for respiratory depression.305
If the required dose of oxycodone myristate extended-release capsules is less than 9 mg of oxycodone, an alternative analgesic should be selected.291
Cautions ⬆ ⬇
Although adverse effects are milder than those of morphine, addiction liability of oxycodone is about the same as that of morphine; oxycodone shares the toxic potentials of the opiate agonists, and the usual precautions of opiate agonist therapy should be observed. (See Cautions in the Opiate Agonists General Statement 28:08.08.) When preparations containing oxycodone in combination with other drugs are administered, the cautions applicable to each ingredient must be considered.
Because oxycodone hydrochloride is commercially available as an oral solution (5 mg/5 mL) and as an oral concentrate solution (100 mg/5 mL), confusion between the different concentrations or between mg and mL can result in accidental overdosage and/or death.299,304 Caution is required to avoid confusing the formulations.299,304 (See Conventional Oxycodone Hydrochloride Formulations under Dosage and Administration: Administration.) The oral concentrate solution should be used only in opiate-tolerant patients.304
Extended-release opiates are associated with a greater risk of overdose and death because of the larger amount of drug contained in each dosage unit.290,291 Oxycodone has been intentionally abused by crushing extended-release preparations and “snorting” the powder or dissolving the contents in water and injecting the solution IV. 290 Abuse by chewing extended-release preparations also has been reported. 290 Breaking, chewing, crushing, or dissolving of extended-release tablets containing oxycodone hydrochloride results in immediate release of the opiate and the risk of a potentially fatal overdose.290,305 Snorting or injecting the dissolved contents of oxycodone myristate extended-release capsules also can result in a potentially fatal overdose.291 The risk of toxicity is increased when oxycodone is used concomitantly with alcohol or other CNS depressants, including other opiates.290,291,303
Oxycodone hydrochloride extended-release tablets (OxyContin®) and oxycodone myristate extended-release capsules (Xtampza® ER) are formulated with physical and chemical properties that are intended to make these dosage forms more difficult to manipulate for IV or intranasal abuse and misuse.290,291 However, abuse by these routes, as well as by the oral route, is still possible.290,291
Because some patients have reported difficulty in swallowing oxycodone hydrochloride extended-release tablets, the tablets should be administered one at a time with enough water to ensure that each tablet is completely swallowed immediately after it is placed in the mouth; the extended-release tablets should not be wet (e.g., soaked, licked) before they are placed in the mouth for swallowing.290 Choking, gagging, regurgitation, tablets stuck in the throat, and, rarely, intestinal obstruction and exacerbation of diverticulitis (sometimes requiring medical intervention to remove the tablet) have been reported.290 Patients with underlying GI disorders (e.g., esophageal or colon cancer) associated with a narrow GI lumen are at greater risk of developing these complications.290 Use of an alternative analgesic should be considered for patients who have difficulty swallowing and in those at risk for underlying GI disorders associated with a narrow GI lumen.290 Because extended-release tablets containing oxycodone hydrochloride in fixed combination with acetaminophen swell and become sticky when wet, the same precautions apply to this formulation.305
Some commercially available formulations of oxycodone hydrochloride contain sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.
The presence of oxycodone is not reliably detected by all urine drug tests for opiates, especially those designed for in-office use, and laboratories may report urine drug concentrations below a specified value as negative results.290,291 If urine testing for oxycodone is used in patient management, the limitations of such testing should be considered and appropriate assay sensitivity and specificity should be ensured.290,291
Oxycodone is distributed into milk.290,291,295,299,302 Because of the possibility of sedation or respiratory depression in breast-fed infants, use of oxycodone in nursing women should be avoided.290,291,299,302 Infants exposed to oxycodone through breast milk should be observed for GI effects, excessive sedation, respiratory depression, and changes in feeding patterns.291,295,303 Symptoms of withdrawal can occur in opiate-dependent breast-fed infants when maternal administration of opiates is discontinued or breast-feeding is stopped.290,291
Drug Interactions ⬆ ⬇
Because oxycodone is metabolized by the cytochrome P-450 (CYP) microsomal enzyme system, principally by isoenzyme 3A4, concomitant use of oxycodone with drugs that inhibit CYP3A4 activity (e.g., macrolide antibiotics [e.g., erythromycin], azole antifungals [e.g., ketoconazole, voriconazole], protease inhibitors [e.g., ritonavir]) may result in reduced clearance and increased plasma concentrations of oxycodone, possibly resulting in increased or prolonged opiate effects, including an increased risk of fatal respiratory depression.290,291,299,302,303 These effects could be more pronounced with concomitant use of oxycodone and inhibitors of both CYP2D6 and CYP3A4 (see Pharmacokinetics), particularly when an inhibitor is added after a stable oxycodone dosage has been achieved.290,291 Concomitant administration of oxycodone hydrochloride (single 10-mg dose as extended-release tablets) and the potent CYP3A4 inhibitor ketoconazole (200 mg twice daily) increased area under the plasma concentration-time curve (AUC) and peak plasma concentration of oxycodone by 170 and 100%, respectively,290,291 while concomitant administration of voriconazole with oxycodone increased the AUC and peak plasma concentration of oxycodone by 3.6- and 1.7-fold, respectively.299,302 However, inhibition of the CYP2D6 pathway alone has not been shown to result in clinically important interactions.290,291,299,303 If concomitant therapy with a CYP3A4 inhibitor is discontinued, a decrease in plasma oxycodone concentrations may occur, potentially decreasing analgesic efficacy or resulting in withdrawal effects.291,303
Concomitant use of oxycodone with CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin) may result in increased clearance and decreased plasma concentrations of oxycodone, with possible lack of efficacy or development of opiate withdrawal.290,291,299,302,303 Concomitant administration of oxycodone and the CYP3A4 inducer rifampin decreased AUC and peak plasma concentration of oxycodone by 86 and 63%, respectively.290,291 If concomitant therapy with a CYP3A4 inducer is discontinued, an increase in plasma oxycodone concentrations may occur, potentially increasing or prolonging therapeutic and adverse effects of the drug and increasing the risk of serious respiratory depression.290,291,303
Therefore, caution should be exercised and patients who require concomitant therapy with a CYP3A4 inhibitor or inducer, or who have recently discontinued such therapy, should be monitored closely at frequent intervals, and dosage adjustments should be considered until stable drug effects are achieved.290,291,299,302,303
For further information about drug interactions involving opiate agonists (including oxycodone), see Drug Interactions in the Opiate Agonists General Statement 28:08.08.
Other Information ⬆ ⬇
Pharmacokinetics
Following oral administration of conventional preparations of oxycodone, the analgesic effect occurs within 10-15 minutes, reaches its maximum in 30-60 minutes, and persists for 3-6 hours. Following oral administration of oxycodone as an extended-release tablet, the onset of analgesia occurred within 1 hour in most patients.300 Oxycodone is extensively metabolized to noroxycodone, oxymorphone, and noroxymorphone and their glucuronide conjugates, with the formation of noroxycodone and oxymorphone mediated by cytochrome P-450 (CYP) isoenzymes 3A and 2D6, respectively; oxycodone and its metabolites are excreted principally in urine.290,291,299,302 Because oxymorphone is present in plasma in only low concentrations following oxycodone administration, it is not thought to contribute substantially to analgesic effects of the drug.290,291,299,302
The oral bioavailability of oxycodone is 60-87%.290,299,302,303 The relative oral bioavailability of extended-release tablets of oxycodone hydrochloride compared with conventional oral preparations is 100%.290 The extended-release tablets are formulated to provide controlled delivery of oxycodone over 12 hours.290 Release of the drug from the extended-release tablets is pH independent.290 Following rectal administration of oxycodone hydrochloride extended-release tablets in healthy adults, the area under the plasma concentration-time curve (AUC) and peak plasma concentration were increased by 39 and 9%, respectively, compared with oral administration.300 With multiple oral dosing, steady-state plasma concentrations usually are achieved within 24-36 hours in healthy individuals receiving extended-release tablets of oxycodone hydrochloride.290 Administration of the extended-release tablets with food does not substantially affect the extent of absorption.290 The apparent elimination half-life following oral administration of the extended-release tablets or conventional preparations is 4.5 or 3.2 hours, respectively.290
Oxycodone myristate extended-release capsules also are formulated to provide delivery of oxycodone over 12 hours but are not bioequivalent to oxycodone hydrochloride extended-release tablets.291 Under fasting conditions, both peak serum concentrations and AUC are lower for the extended-release capsules; under fed conditions, peak serum concentrations are lower, but AUC is similar to values for the extended-release tablets.291 Mean peak serum concentrations of oxycodone are lower (73 and 43% lower for administration under fasting and fed conditions, respectively) and the median time to peak serum concentration is approximately 3 hours longer when the drug is administered as extended-release capsules compared with administration as an oral solution in the fasting state.291 The relative oral bioavailability of oxycodone myristate extended-release capsules compared with an oral solution of the drug is lower in the fasting state (75%) but comparable in the fed state (114%).291 The time to peak plasma concentrations is approximately 4.5 hours following administration of the extended-release capsules under fed conditions.291 With repeated administration in healthy individuals, steady-state concentrations are achieved within 24-36 hours.291 The apparent elimination half-life following oral administration of the extended-release capsules under fed conditions is 5.6 hours, compared with 3.2 hours following administration of conventional preparations of the drug.291
Bioavailability of oxycodone myristate extended-release capsules is increased by administration with food and is dependent on the content of the meal.291 When the extended-release capsules are administered following a high-fat, high-calorie meal rather than in the fasted state, peak concentrations and AUC are increased by 100-150 and 50-60%, respectively; when administered following a medium-fat, medium-calorie meal, peak concentrations and AUC are increased by 84 and 28%, respectively.291 When the extended-release capsules are administered following a low-fat, low-calorie meal, peak concentrations are 19% higher and AUC is comparable to values following administration under fasting conditions.291 The pharmacokinetic profile for the capsule contents sprinkled on food is equivalent to that for the intact capsule administered with food.291
Extended-release tablets containing oxycodone hydrochloride in fixed combination with acetaminophen are available as a bilayer formulation in which a portion of the labeled oxycodone hydrochloride and acetaminophen doses is contained in an immediate-release layer and the remaining portion is contained in a layer that slowly releases the drugs.305 Following single or multiple doses of this formulation, the bioavailability (dose-normalized AUC and peak plasma concentration) of oxycodone is comparable to that of conventional preparations of the drug.305 Oxycodone is detectable in plasma within 30 minutes following administration of the fixed-combination extended-release tablets; peak concentrations are achieved in 3-4 hours.305 Following administration every 12 hours, steady-state concentrations are attained within 24 hours.305 Administration of this fixed-combination extended-release formulation with a low-fat or high-fat meal delayed peak concentrations by 1 or 2 hours, respectively; increased mean AUC by 15-16%; and increased peak concentrations by 12-25%.305 The apparent elimination half-life of oxycodone following oral administration of the fixed-combination extended-release tablets is 4.5 hours, compared with 3.9 hours following administration of conventional preparations of the drug.305
Following oral administration of oxycodone hydrochloride extended-release tablets in patients with renal impairment (creatinine clearance less than 60 mL/minute), peak plasma concentrations of the drug and its noroxycodone metabolite were 50 and 20% higher, respectively, and AUCs of oxycodone, noroxycodone, and oxymorphone were 60, 50, and 40% higher, respectively, than values in individuals with normal renal function.290,291 The elimination half-life of oxycodone was increased by 1 hour in patients with renal impairment compared with individuals with normal renal function.290,291
Administration of oxycodone hydrochloride extended-release tablets to patients with mild to moderate hepatic impairment resulted in increases in peak plasma concentrations and AUCs of oxycodone (50 and 95%, respectively) and noroxycodone (20 and 65%, respectively) but decreases in peak plasma concentrations and AUC of oxymorphone (30 and 40%, respectively).290,291 The elimination half-life of oxycodone was increased by 2.3 hours in patients with mild to moderate hepatic impairment compared with individuals with normal hepatic function.290,291
Chemistry and Stability
Chemistry
Oxycodone is a synthetic phenanthrene-derivative opiate agonist. The drug differs structurally from hydrocodone only in the attachment of a hydroxyl group to carbon 14 on the phenanthrene nucleus. Oxycodone occurs as long rods or as tautomeric, strongly refringent scales and is insoluble in water and soluble in alcohol. Oxycodone is commercially available as the hydrochloride or myristate salt; the hydrochloride salt is freely soluble in water and slightly soluble in alcohol. Oxycodone hydrochloride oral solution has a pH of 1.4-4.
Oxycodone myristate extended-release capsules contain extended-release microspheres in which oxycodone is present as a solid solution of a fatty acid salt (oxycodone myristate) in a hydrophobic matrix that also contains waxes.294 Homogeneous dispersion of the drug in the form of a solid solution in fatty acid and waxes imparts extended-release properties.294
Extended-release tablets containing oxycodone hydrochloride in fixed combination with acetaminophen are available as a bilayer formulation in which a portion of the labeled oxycodone hydrochloride and acetaminophen doses is contained in an immediate-release layer and the remaining portion is contained in a layer that slowly releases the drugs.305 The tablets are designed to swell in gastric fluid and gradually release the extended-release components.305
Stability
Oxycodone preparations should be stored in tight containers and generally should be protected from light and stored at 15-30°C.
Additional Information
For further information on chemistry, pharmacology, pharmacokinetics, uses, cautions, chronic toxicity, acute toxicity, drug interactions, and dosage and administration of oxycodone, see the Opiate Agonists General Statement 28:08.08.
Preparations ⬆ ⬇
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Oxycodone preparations are subject to control under the Federal Controlled Substances Act of 1970 as schedule II (C-II) drugs.
oxyCODONE Hydrochloride
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
oxyCODONE and Acetaminophen
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|
Oral | Solution | 5 mg/5 mL Oxycodone Hydrochloride and Acetaminophen 325 mg/5 mL | Roxicet® (C-II) | Roxane |
| Tablets | 2.5 mg Oxycodone Hydrochloride and Acetaminophen 300 mg* | oxyCODONE Hydrochloride and Acetaminophen Tablets (C-II) | |
| | 2.5 mg Oxycodone Hydrochloride and Acetaminophen 325 mg* | oxyCODONE Hydrochloride and Acetaminophen Tablets (C-II) | |
| | | Percocet® (C-II) | Endo |
| | 5 mg Oxycodone Hydrochloride and Acetaminophen 300 mg* | oxyCODONE Hydrochloride and Acetaminophen Tablets | |
| | | Primlev® (C-II) | Akrimax |
| | 5 mg Oxycodone Hydrochloride and Acetaminophen 325 mg* | Endocet® (C-II; scored) | Qualitest |
| | | oxyCODONE Hydrochloride and Acetaminophen Tablets (C-II) | |
| | | Percocet® (C-II; scored) | Endo |
| | 7.5 mg Oxycodone Hydrochloride and Acetaminophen 300 mg* | oxyCODONE Hydrochloride and Acetaminophen Tablets (C-II) | |
| | | Primlev® (C-II) | Akrimax |
| | 7.5 mg Oxycodone Hydrochloride and Acetaminophen 325 mg* | Endocet® (C-II) | Qualitest |
| | | oxyCODONE Hydrochloride and Acetaminophen Tablets (C-II) | |
| | | Percocet® (C-II) | Endo |
| | 10 mg Oxycodone Hydrochloride and Acetaminophen 300 mg* | oxyCODONE Hydrochloride and Acetaminophen Tablets (C-II) | |
| | | Primlev® (C-II) | Akrimax |
| | 10 mg Oxycodone Hydrochloride and Acetaminophen 325 mg* | Endocet® (C-II) | Qualitest |
| | | oxyCODONE Hydrochloride and Acetaminophen Tablets (C-II) | |
| | | Percocet® (C-II) | Endo |
| Tablets, extended-release, film-coated | 7.5 mg Oxycodone Hydrochloride and Acetaminophen 325 mg | Xartemis® XR (C-II) | Mallinckrodt |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
oxyCODONE and Aspirin
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Other oxyCODONE Hydrochloride Combinations
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|
Oral | Tablets, film-coated | 5 mg with Ibuprofen 400 mg* | oxyCODONE Hydrochloride and Ibuprofen Film-coated Tablets (C-II) | |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
oxyCODONE Myristate
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|
Oral | Capsules, extended-release | 9 mg (of oxycodone [equivalent to 10 mg oxycodone hydrochloride]) | Xtampza® ER (C-II) | Collegium |
| | 13.5 mg (of oxycodone [equivalent to 15 mg oxycodone hydrochloride]) | Xtampza® ER (C-II) | Collegium |
| | 18 mg (of oxycodone [equivalent to 20 mg oxycodone hydrochloride]) | Xtampza® ER (C-II) | Collegium |
| | 27 mg (of oxycodone [equivalent to 30 mg oxycodone hydrochloride]) | Xtampza® ER (C-II) | Collegium |
| | 36 mg (of oxycodone [equivalent to 40 mg oxycodone hydrochloride]) | Xtampza® ER (C-II) | Collegium |
Copyright ⬆ ⬇
AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions April 19, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
References ⬆
Only references cited for selected revisions after 1984 are available electronically.
117. Jackson KC II, Lipman AG. Nonopioid analgesics. In: Lipman AG, ed. Pain management for primary care clinicians. Bethesda, MD: American Society of Health-System Pharmacists; 2004:43-58.
118. Cranmer KW, Mason M. Special considerations in geriatric pain management. In: Lipman AG, ed. Pain management for primary care clinicians. Bethesda, MD: American Society of Health-System Pharmacists; 2004:219-232.
119. Fakata KL, Miaskowski C, Lipman AG. Chronic malignant pain. In: Lipman AG, ed. Pain management for primary care clinicians. Bethesda, MD: American Society of Health-System Pharmacists; 2004:139-52.
120. McNicol E, Carr DB. Pharmacological treatment of pain. In: McCarberg B, Passik SD, eds. Expert guide to pain management. Philadelphia: American College of Physicians; 2005:145-78.
121. American Pain Society. Principles of analgesic use in the treatment of acute pain and cancer pain. 5th edition. Glenview, IL; 2003:3,9,13,14.
288. US Food and Drug Administration. All manufacturers of prescription combination drug products with more than 325 mg of acetaminophen have discontinued marketing. Rockville, MD; 2014 Mar 26. [Web]
289. US Food and Drug Administration. Prescription drug products containing acetaminophen; actions to reduce liver injury from unintentional overdose. Notice. [Docket No. FDA-2011-N-0021] Fed Regist . 2011; 76:2691-7.
290. Purdue Pharma. Oxycontin® (oxycodone hydrochloride) extended-release tablets prescribing information. Stamford, CT; 2015 Aug.
291. Collegium Pharmaceuticals. Xtampza® ER (oxycodone) extended-release capsules prescribing information. Canton, MA; 2016 Apr.
294. Collegium Pharmaceutical. Xtampza ER briefing document from the joint meeting of the Anesthetic and Analgesic Drug Products Advisory Committee and the Drug Safety and Risk Management Advisory Committee. 2015 Sep 11. [Web]
295. Briggs GG, Freeman RK. Oxycodone. In: Drugs in pregnancy and lactation: a reference guide to fetal and neonatal risk. 10th ed. Philadelphia, PA: Wolters Kluwer; 2015: 1040-1.
296. Gal P, Reed MD. Medications: In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds. Nelson textbook of pediatrics. 18th ed. Philadelphia: Saunders; 2007: 2955-97.
297. Lugo RA, Kern SE. Pharmacokinetics of opioids in the management of pain. In: Lipman AG, ed. Pain management for primary care clinicians. Bethesda, MD: American Society of Health-System Pharmacists; 2004.
298. Engoron B, Flerlage J, eds. The Harriet Lane handbook: a manual for pediatric house officers. 20th ed. Philadelphia, PA: Saunders; 2015: 889.
299. Roxane Laboratories, Inc. Oxycodone hydrochloride oral solution prescribing information. Columbus, OH; 2015 Jan.
300. Purdue Pharma L.P. Oxycontin® (oxycodone HCl controlled release) tablets prescribing information. Stamford, CT; 2001 Jul.
301. Broussard CS, Rasmussen SA, Reefhuis J et al. Maternal treatment with opioid analgesics and risk for birth defects. Am J Obstet Gynecol . 2011; 204:314.e1-11.
302. Egalet US, Inc. Oxaydo® (oxycodone hydrochloride) tablets prescribing information. Wayne, PA; 2015 Apr.
303. Endo Pharmaceuticals. Percocet® (oxycodone and acetaminophen) tablets prescribing information. Malvern, PA; 2016 Mar.
304. Gavis Pharmaceuticals. Oxycodone hydrochloride solution for oral use prescribing information. Somerset, NJ; 2014 Oct.
305. Mallinckrodt. Xartemis® XR (oxycodone hydrochloride and acetaminophen) extended-release tablets prescribing information, Hazelwood, MO; 2015 Mar.
400. US Food and Drug Administration. Drug safety communication: FDA warns about several safety issues with opioid pain medicines; requires label changes. Silver Spring, MD; 2016 Mar 22. From FDA website. [Web]
401. Katz N, Mazer NA. The impact of opioids on the endocrine system. Clin J Pain . 2009; 25:170-5. [PubMed 19333165]
402. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL et al. Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer . 2004; 100:851-8. [PubMed 14770444]
403. Abs R, Verhelst J, Maeyaert J et al. Endocrine consequences of long-term intrathecal administration of opioids. J Clin Endocrinol Metab . 2000; 85:2215-22. [PubMed 10852454]
404. Fraser LA, Morrison D, Morley-Forster P et al. Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women. Exp Clin Endocrinol Diabetes . 2009; 117:38-43. [PubMed 18523930]
410. Nuckols TK, Anderson L, Popescu I et al. Opioid prescribing: a systematic review and critical appraisal of guidelines for chronic pain. Ann Intern Med . 2014; 160:38-47. [PubMed 24217469]
411. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016. MMWR Recomm Rep . 2016; 65:1-49. [PubMed 26987082]
412. Chou R, Fanciullo GJ, Fine PG et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain . 2009; 10:113-30. [PubMedCentral][PubMed 19187889]
413. Management of Opioid Therapy for Chronic Pain Working Group, US Department of Veterans Affairs and Department of Defense. VA/DoD clinical practice guideline for management of opioid therapy for chronic pain. 2010 May. [Web]
414. Chou R, Cruciani RA, Fiellin DA et al. Methadone safety: a clinical practice guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. J Pain . 2014; 15:321-37. [PubMed 24685458]
415. Manchikanti L, Abdi S, Atluri S et al. American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: Part 2--guidance. Pain Physician . 2012; 15(3 Suppl):S67-116.
416. Park TW, Saitz R, Ganoczy D et al. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study. BMJ . 2015; 350:h2698. [PubMedCentral][PubMed 26063215]
417. Jones CM, McAninch JK. Emergency Department Visits and Overdose Deaths From Combined Use of Opioids and Benzodiazepines. Am J Prev Med . 2015; 49:493-501. [PubMed 26143953]
418. Dasgupta N, Funk MJ, Proescholdbell S et al. Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose Mortality. Pain Med . 2016; 17:85-98. [PubMed 26333030]
419. Prescription Drug Monitoring Program Training and Technical Assistance Center (PDMP TTAC). Criteria for mandatory enrollment or query of PDMP. From PDMP TTAC website. Accessed 2016 Sep 14. [Web]
420. National Alliance for Model State Drug Laws (NAMSLD). Overview of state pain management and prescribing policies. From NAMSLD webiste. Accessed 2016 Sep 14. [Web]
421. Bennett A (Maine Office of Governor). Augusta, ME: 2016 Apr 19. Governor signs major opioid prescribing reform bill. Press release. [Web]
422. American Academy of Pain Medicine (AAPM). Use of opioids for the treatment of chronic pain. A statement from the American Academy of Pain Medicine. From AAPM website. 2013 Feb. [Web]
423. Franklin GM, American Academy of Neurology. Opioids for chronic noncancer pain: a position paper of the American Academy of Neurology. Neurology . 2014; 83:1277-84. [PubMed 25267983]
424. Dunn KM, Saunders KW, Rutter CM et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med . 2010; 152:85-92. [PubMedCentral][PubMed 20083827]
425. Gomes T, Mamdani MM, Dhalla IA et al. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med . 2011; 171:686-91. [PubMed 21482846]
426. Bohnert AS, Valenstein M, Bair MJ et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA . 2011; 305:1315-21. [PubMed 21467284]
429. Paice JA, Portenoy R, Lacchetti C et al. Management of Chronic Pain in Survivors of Adult Cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol . 2016; 34:3325-45. [PubMed 27458286]
430. Chou R, Gordon DB, de Leon-Casasola OA et al. Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain . 2016; 17:131-57. [PubMed 26827847]
431. Washington State Agency Medical Directors' Group (AMDG). Interagency guideline on prescribing opioids for pain, 3rd ed. From Washington State AMDG website. 2015 Jun. [Web]
432. Hegmann KT, Weiss MS, Bowden K et al. ACOEM practice guidelines: opioids for treatment of acute, subacute, chronic, and postoperative pain. J Occup Environ Med . 2014; 56:e143-59.
433. Cantrill SV, Brown MD, Carlisle RJ et al. Clinical policy: critical issues in the prescribing of opioids for adult patients in the emergency department. Ann Emerg Med . 2012; 60:499-525. [PubMed 23010181]
434. Thorson D, Biewen P, Bonte B et al, for Institute for Clinical Systems Improvement (ICSI). Acute pain assessment and opioid prescribing protocol. From ICSI website. 2014 Jan. [Web]
435. New York City Department of Health and Mental Hygiene. New York City emergency department discharge opioid prescribing guidelines. From NYC Health website. 2013 Jan. [Web]
436. Chou R, Deyo R, Devine B et al. The effectiveness and risks of long-term opioid treatment of chronic pain. Evidence report/technology assessment No. 218. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); 2014 Sep. [Web]
500. FDA drug safety communication . FDA updates prescribing information for all opioid pain medicines to provide additional guidance for safe use Includes updates to help reduce unnecessary prescribing; issued Apr 13 2023. From FDA website. [Web]
700. US Food and Drug Administration. Drug safety communication: FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning. Silver Spring, MD; 2016 Aug 31. From FDA website. [Web]
701. Jones CM, Mack KA, Paulozzi LJ. Pharmaceutical overdose deaths, United States, 2010. JAMA . 2013; 309:657-9. [PubMed 23423407]
702. Jones CM, Paulozzi LJ, Mack KA et al. Alcohol involvement in opioid pain reliever and benzodiazepine drug abuse-related emergency department visits and drug-related deaths - United States, 2010. MMWR Morb Mortal Wkly Rep . 2014; 63:881-5. [PubMedCentral][PubMed 25299603]
703. Hertz S. Letter to manufacturers of opioid analgesics: safety labeling change notification. Silver Spring, MD: US Food and Drug Administration. Accessed 2017 Mar 20. [Web]
704. Purdue Pharma. Oxycontin® (oxycodone hydrochloride) extended-release tablets prescribing information. Stamford, CT; 2016 Dec.
750. Food and Drug Administration. FDA Drug Safety Communication: FDA recommends health care professionals discuss naloxone with all patients when prescribing opioid pain relievers or medicines to treat opioid use disorder; consider prescribing naloxone to those at increased risk of opioid overdose. 2020 Jul 23. From FDA website. Accessed 2020 Jul 28. [Web]