section name header

Introduction

VA Class:CN101

AHFS Class:

Associated Monographs

Notification

  • 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.

Opiate agonists encompass a group of naturally occurring, semisynthetic, and synthetic drugs that stimulate opiate receptors and effectively relieve pain without producing loss of consciousness.

Uses

[Section Outline]

Pain !!navigator!!

Opiate agonists are generally used to provide temporary analgesia in the symptomatic treatment of moderate to severe pain such as that associated with acute and some chronic medical disorders including renal or biliary colic, myocardial infarction (MI), acute trauma, postoperative pain, and terminal cancer. Opiate analgesics increasingly have been used for the management of chronic noncancer pain despite uncertainty over the long-term benefits of such therapy.413,415,431,436 The drugs may also be used to provide analgesia during diagnostic and orthopedic procedures and during labor. In patients with acute pulmonary edema, opiate agonists are used for their cardiovascular effects and to relieve anxiety associated with this condition. The drugs are also used to provide preoperative sedation and as a supplement to anesthesia. Although most of the opiate agonists produce similar analgesia in equianalgesic doses, such factors as oral effectiveness, duration of action, other CNS effects such as euphoria or sedation, degree of action on smooth muscle, and individual variation in patient response should be considered in the selection of a specific opiate agonist.

Some opiates have been used in the treatment of pain in various combinations with nonsteroidal anti-inflammatory agents (NSAIAs), acetaminophen, and/or caffeine. Opiates (e.g., codeine, oxycodone, hydrocodone) given orally in combination with acetaminophen or NSAIAs may produce a greater analgesic effect than that produced by either drug used individually. There also is some evidence that acetaminophen or NSAIAs in combination with oral doses of an opiate may cause fewer adverse effects than equianalgesic doses of the individual drugs alone.

Various extended-release and long-acting opiate analgesics are used for the management of pain that is severe enough to require long-term, daily, around-the-clock use of an opiate analgesic.262,263 Because of the risks of addiction, abuse, and misuse associated with opiates, even at recommended doses, and because of the greater risks of overdose and death with extended-release and long-acting opiate formulations, these extended-release and long-acting opiate analgesics should be reserved for use in patients for whom alternative treatment options (e.g., nonopiate analgesics or immediate-release opiates) are inadequate or not tolerated.262,263 These preparations are not indicated for use on an as-needed (“prn”) basis.262,263 Some extended-release or long-acting preparations or dosage strengths should be used only in opiate-tolerant patients (see the individual monographs in 28:08.08).260,264,267 Patients 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 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.262

Because of the risks associated with opiate overdosage, clinicians should routinely discuss the availability of the opiate antagonist naloxone with all patients receiving new or reauthorized prescriptions for opiate analgesics.750 Clinicians should consider prescribing naloxone for patients receiving opiate analgesics who are at increased risk of opiate overdosage411,431,750 or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.750 (See Cautions: Precautions and Contraindications.)

Chronic Pain

Chronic Noncancer Pain

In patients with chronic pain (generally defined as pain lasting longer than 3 months or past the time of normal tissue healing410,411,412,413 ) that is not associated with active cancer treatment, palliative care, or end-of-life care (also referred to as chronic noncancer pain), opiate analgesics generally should be used only if other appropriate pain management strategies (nonpharmacologic and nonopiate pharmacologic therapies) have been ineffective and the expected benefits of opiate analgesics for both pain relief and functional improvement are anticipated to outweigh the risks.411,412,413,414,422,429 If opiate analgesics are used, they should be part of an integrated approach that also includes appropriate nonpharmacologic modalities (e.g., cognitive-behavioral therapy, relaxation techniques, biofeedback, functional restoration, exercise therapy, certain interventional procedures) and other appropriate pharmacologic therapies (e.g., nonopiate analgesics, analgesic adjuncts such as selected anticonvulsants and antidepressants for certain neuropathic pain conditions).411,412,413,422,429

Use of opiate analgesics for the management of chronic noncancer pain has increased despite uncertainty over the long-term benefits of such therapy.413,415,431,436 Clinical trials of opiate analgesics in the symptomatic treatment of chronic pain generally have been of short duration, and available evidence is insufficient to determine whether long-term opiate therapy results in sustained pain relief or improvements in function and quality of life.411,423,431,432,436 In addition, evidence that opiate analgesics are superior to other pharmacologic or nonpharmacologic treatments for chronic pain generally is lacking.432 However, use of opiate analgesics is associated with serious risks (e.g., opiate use disorder, overdose).411,431,436 Prior to initiation of opiate therapy for chronic noncancer pain, patients should undergo thorough evaluation, including assessment of risk factors for misuse, abuse, and addiction.411,412,413,415,422,429 Clinicians should establish treatment goals with all patients, including realistic goals for pain and function, and should consider how therapy will be discontinued if benefits do not outweigh risks.411,415 Initial opiate therapy for chronic noncancer pain should be regarded as a therapeutic trial that will be continued only if there are clinically meaningful improvements in pain and function that outweigh the risks of therapy.411,412,413 Prior to and periodically during therapy, clinicians should discuss with patients known risks and realistic benefits of such therapy and patient and clinician responsibilities for managing therapy.411,412,413,414,415

Although specific recommendations for the management of opiate therapy for chronic noncancer pain vary across clinical practice guidelines, common elements include risk mitigation strategies, upper dosage thresholds, careful dosage titration, and consideration of risks associated with particular opiates and formulations, coexisting diseases, and concomitant drug therapy.410,411,414,415,423

Some experts recommend that opiate therapy for chronic noncancer pain be initiated with conventional (immediate-release) opiate analgesics prescribed at the lowest effective dosage.411,415 Opiate selection, initial dosage, and dosage titration should be individualized according to the patient's health status, prior opiate use, attainment of therapeutic goals, and predicted or observed harms.412,413 Experts generally agree that methadone should be prescribed for the management of chronic pain only by clinicians who are knowledgeable about its risks (e.g., QT-interval prolongation) and pharmacokinetic properties,410,411,412,413,414,415 and should not be the first choice for an extended-release or long-acting opiate analgesic.411,415 Similarly, fentanyl transdermal system should be prescribed only by clinicians who are familiar with the absorption characteristics and dosing of this formulation.411

Benefits and harms of opiate analgesic therapy should be evaluated within 1-4 weeks following initiation of therapy or an increase in dosage411,413 and reevaluated on an ongoing basis (e.g., at least every 3 months411 ) throughout therapy.411,412,413 Monitoring should include documentation of pain intensity and level of functioning, assessment of progress toward therapeutic goals, presence of adverse effects, and adherence to prescribed therapies.412,413,422,423 Common opiate-related adverse effects (e.g., constipation, nausea and vomiting, cognitive and psychomotor impairment) should be anticipated and appropriately managed.412,413,415 If benefits do not outweigh harms, other therapies should be optimized and opiate therapy should be tapered to a lower dosage or tapered and discontinued.411,412,413,415

When repeated increases in dosage are required, potential causes should be evaluated and the relative benefits and risks reassessed.412,413 Although evidence is limited, some experts state that a trial of opiate rotation may be considered in patients experiencing intolerable adverse effects or inadequate benefit despite increases in dosage.412,413,415 Although the dosage level that constitutes high-dose therapy varies across clinical practice guidelines, there is agreement that use of higher dosages requires particular caution,410,412,415 including more frequent and intensive monitoring or referral to a specialist.411,412,413 (See Dosage and Administration: Dosage.) Greater benefits of high-dose opiate therapy for chronic pain have not been established in controlled clinical studies, and higher dosages have been associated with increased risks of motor vehicle accidents, overdosage, and opiate use disorder.411,415,423,424,425,426

Various strategies for managing risks associated with opiate therapy for chronic noncancer pain have been recommended, including written treatment agreements or plans (e.g., “contracts”), urine drug testing, review of state prescription drug monitoring program (PDMP) data, and risk assessment and monitoring tools.410,411,412,413,414,415,422,423,429 Although precise recommendations may vary, recent clinical practice guidelines generally recommend such monitoring in all patients receiving opiate therapy for chronic noncancer pain, although the frequency and intensity of monitoring may vary depending on risk assessments.411,413,414,415,422,423,429 Urine drug testing may be used at baseline and periodically during therapy to assess adherence to the treatment plan and to screen for use of other prescription or illicit drugs.411,412,413,414,415 Baseline and periodic review of the patient's history of controlled substance prescriptions using state PDMP data also may assist in reducing prescription drug abuse and in identifying opiate dosages or drug combinations (e.g., benzodiazepines) that increase the risk for overdosage.411,415 (See Drug Interactions: Benzodiazepines and Other CNS Depressants.) Opiate therapy should be tapered and discontinued in patients who engage in serious or repeated aberrant drug-related behaviors or drug abuse or diversion.412,413,415 Clinicians should offer or arrange treatment for patients with opiate use disorder.411,412,413

Chronic Cancer Pain

In the management of severe, chronic pain associated with a terminal illness such as cancer, the principal goal of analgesic therapy is to make the patient relatively pain-free while maintaining as good a quality of life as possible. Analgesic therapy must be individualized and titrated according to patient response and tolerance. When nonopiate or combinations of nonopiate and opiate analgesics are ineffective, oral administration of an opiate agonist on a regular schedule generally will provide adequate relief of severe, chronic pain and the fear of its recurrence. Extended-release and long-acting preparations are used orally for the management of such pain when it is severe enough to require long-term, daily, around-the-clock use of an opiate analgesic and when alternative treatment options (e.g., nonopiate analgesics or immediate-release opiates) are inadequate or not tolerated.262,263 Although consideration of the dependence potential of opiate agonists has often limited their effective use by many clinicians in terminally ill patients with severe, chronic pain, such consideration is irrelevant in the context of terminal illness. When oral opiate agonists no longer provide adequate relief or in patients unable to swallow or tolerate oral drugs, alternative methods of administration such as subcutaneous, rectal, continuous IV infusion, patient-controlled IV infusion, epidural, intrathecal, or transdermal systems should be considered.

Acute Pain

In the symptomatic treatment of acute pain, opiate analgesics generally should be reserved for pain resulting from severe injuries or medical conditions, surgical procedures, or when nonopiate alternatives for relieving pain and restoring function are expected to be ineffective or are contraindicated.431,432,433,435 Concomitant use of other appropriate therapies should be optimized.432,434,435 Because long-term opiate use often begins with the treatment of acute pain, conventional (immediate-release) opiates should be used in the smallest effective dosage and for the shortest possible duration when opiate analgesia is required for symptomatic treatment of acute pain.411,431,434,435 When sufficient for pain management, lower-potency opiate analgesics given in conjunction with acetaminophen or an NSAIA on an as-needed (“prn”) basis have been recommended.432 The prescribed quantity of opiate analgesics 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, for acute pain not related to trauma or surgery.411,433,434,435 Clinicians should not prescribe larger quantities of opiate analgesics for use in the event that pain continues longer than expected;411,432 instead, patients should be reevaluated if severe acute pain does not remit.411,431,435

When opiate analgesics are used to alleviate moderate to severe postoperative pain, opiate therapy should be provided as part of a multimodal regimen that also includes acetaminophen and/or NSAIAs and other pharmacologic (e.g., certain anticonvulsants, regional local anesthetic techniques) and nonpharmacologic therapy as appropriate.430,431,432 In the management of postoperative pain, scheduled administration of nonopiate analgesics is recommended to reduce use of opiate analgesics and provide more-consistent analgesia.430,431 Oral administration of conventional opiate analgesics generally is preferred over IV administration in patients who can tolerate oral therapy.430,431 Scheduled (around-the-clock) dosing of opiate analgesics frequently is required during the immediate postoperative period or following major surgery.430,432 When repeated parenteral administration is required, IV patient-controlled analgesia (PCA) generally is recommended.430,431 Routine use of continuous (basal) IV infusions of opiates in opiate-naive patients receiving PCA is not recommended.430,431 IM administration of opiate analgesics is discouraged because IM injections can cause pain and are associated with unreliable absorption, resulting in inconsistent postoperative analgesia.430

Pain that will likely be of short duration, such as that associated with diagnostic procedures or orthopedic manipulation, should be controlled with a short-acting opiate agonist such as fentanyl. Severe but intermittent pain such as may occur in patients with renal colic should also be treated with an opiate agonist providing short-duration analgesia. In bronchoscopy, a drug with good antitussive activity such as morphine may be preferred. Opiate agonists have been used in the treatment of pain of biliary or pancreatic origin. Although it may seem illogical to treat pain of biliary origin with drugs that increase biliary pressure and spasm, these biliary effects do not always occur with therapeutic doses and sedation produced by opiate agonists may contribute to relief of pain.

When administered during labor, opiate agonists should effectively relieve pain without interfering with the progress of labor or normal respiration in the neonate. The closer to delivery the drug is given, the greater the possibility of respiratory depression in the neonate.

Acute Coronary Syndromes

Opiate agonists, principally morphine, are used to relieve pain and anxiety associated with acute coronary syndromes (ACS).527,1100 Although morphine usually is considered the drug of choice in relieving pain associated with MI, other strong opiate agonists such as meperidine, hydromorphone, and levorphanol tartrate also have been used.

Because of its ability to alleviate the work of breathing, reduce anxiety, and favorably affect ventricular loading conditions, morphine is considered the analgesic agent of choice in patients with ST-segment-elevation MI (STEMI).527 In addition to its potent analgesic and anxiolytic effects, morphine also exhibits favorable hemodynamic effects by causing venodilation and modest reductions in heart rate and systolic blood pressure.1100 These properties also may be beneficial in patients with non-ST-segment-elevation ACS (NSTE ACS; unstable angina or non-ST-segment-elevation MI [NSTEMI]); although randomized controlled studies specifically evaluating the use of morphine in patients with NSTE ACS have not been conducted, experts state that it may be reasonable to administer IV morphine in such patients who have continued pain despite treatment with maximally tolerated anti-ischemic drugs (e.g., nitrates).1100 However, use of morphine should not preclude the use of other anti-ischemic drugs with proven benefit.1100 Patients with acute MI typically exhibit overactivity of the sympathetic nervous system, which adversely increases myocardial oxygen demand via acceleration of heart rate, elevation in arterial blood pressure, augmentation of cardiac contractility, and heightened tendency to develop ventricular tachyarrhythmias.140 This increased sympathetic activity results from combined ischemic-type chest discomfort and anxiety, and the principal objective of therapy is to administer sufficient doses of an analgesic such as morphine to relieve what many patients describe as a feeling of impending doom.140 The dose of morphine sulfate needed to achieve adequate pain control is dependent upon several factors such as patient age (e.g., lower doses are recommended in geriatric patients), body size, blood pressure, and heart rate.527 In patients with STEMI, an initial morphine sulfate dose of 4-8 mg IV is recommended, with additional doses of 2-8 mg administered every 5-15 minutes as needed.527 In patients with NSTE ACS, experts state that a morphine sulfate dose of 1-5 mg IV may be administered during IV nitroglycerin therapy and repeated every 5-30 minutes to relieve symptoms and maintain patient comfort.1100

Pain in Critically Ill Patients

Opiate agonists may be used in combination with sedative agents to maintain an optimal level of comfort and safety in patients in a critical care setting.174 Some clinicians state that pain assessment and subsequent documentation using standard assessment tools (e.g., numeric rating scale) should be performed regularly to monitor the patient's response to analgesic therapy.174 If patients are unable to communicate, their pain should be assessed by subjective observations of pain-related behaviors (e.g., movement, facial expression, posturing) and physiologic indicators (e.g., heart rate, blood pressure, respiratory rate).174 To ensure consistent analgesic therapy, a therapeutic plan and goal of analgesia should be established for each patient and communicated to all caregivers.174 Analgesics, including opiate agonists, should be administered on a continuous or scheduled intermittent basis, with supplemental doses given as required.174 If IV administration is required, some clinicians state that fentanyl, hydromorphone, or morphine are the recommended agents.174 In addition, fentanyl is recommended for use in acutely distressed patients because of its rapid onset of analgesia, and morphine or hydromorphone is preferred for intermittent therapy because of their longer duration of action.174 Fentanyl or hydromorphone also is recommended for use in critically ill patients who have hemodynamic instability or renal insufficiency.174 The potential for withdrawal symptoms should be considered in patients receiving high dosages of opiate agonists or longer than 7 days of continuous opiate agonist therapy and the dosage should be tapered systematically to prevent manifestations of opiate withdrawal.174

Vascular Headaches

Opiate agonists are not recommended for routine use in the management of acute migraine attacks because evidence of superiority over other standard therapies (e.g., serotonin type 1 [5-HT1] receptor agonists [triptans], NSAIAs) generally is lacking and because of the risk of medication overuse headache with frequent use, risk of dependence and abuse, and potential for opiate withdrawal syndrome following drug discontinuance.413,415,423,427,428 Some clinicians state that infrequent use of a short-acting opiate or fixed-combination preparation (e.g., acetaminophen and tramadol, codeine-containing fixed combinations) may be considered for abortive therapy of moderate to severe acute migraine attacks when standard therapies are ineffective or not tolerated or as rescue therapy when the patient's usual therapy fails.413,427 For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:32.28.

Delirium !!navigator!!

The American Psychiatric Association (APA) states that opiate agonists, including morphine, may be used in the palliative management of delirium which may have been aggravated by pain.141 However, some opiate agonists (e.g., fentanyl, meperidine) can exacerbate delirium, because their metabolites may exhibit anticholinergic activity.141 For information on the management of delirium, see Uses: Delirium, in Haloperidol 28:16.08.08.

Acute Pulmonary Edema !!navigator!!

Morphine and other strong opiate agonists including meperidine, oxymorphone, and hydromorphone have been used to relieve anxiety in patients with dyspnea associated with acute pulmonary edema and acute left ventricular failure. These drugs should not be used in the treatment of pulmonary edema resulting from a chemical respiratory irritant. Opiate agonists cause pooling of blood in the extremities by decreasing peripheral resistance. This effect results in decreases in venous return, cardiac work, and pulmonary venous pressure, and blood is shifted from the central to peripheral circulation.

Preoperative Sedation !!navigator!!

Routine use of opiate agonists for preoperative sedation in patients without pain is not recommended. Preoperative use of opiate agonists may cause serious complications, usually involving the respiratory or circulatory systems, during surgery and increases the incidence of adverse effects after surgery. The usefulness of mixtures of opiate agonists and antagonists in preanesthetic medication, during surgery, or postoperatively to prevent respiratory depression has not been confirmed by well-controlled clinical studies.

Cough !!navigator!!

Some opiate agonists, notably codeine and its derivative hydrocodone, are used as cough suppressants. For a discussion of opiate agonists as antitussive agents, see Codeine 48:08 and Hydrocodone 48:08. Diphenoxylate and opium preparations are used mainly as antidiarrheal agents (see 56:08).

Detoxification and Maintenance of Opiate Dependence !!navigator!!

Methadone is used in detoxification treatment as an oral substitute for heroin or other morphine-like drugs to suppress the opiate-agonist abstinence syndrome in patients who are dependent on these drugs. If more prolonged suppressive therapy is necessary, methadone or buprenorphine hydrochloride can be used as oral substitutes for maintenance treatment of opiate dependence (opiate use disorder [OUD]). Levomethadyl acetate also has been used for the management of opiate dependence but is no longer commercially available in the US because of potentially severe adverse cardiac effects.183 (See Chronic Toxicity, see Cautions: Precautions and Contraindications, and also see Methadone Hydrochloride 28:08.08 and Buprenorphine Hydrochloride 28:02.12.)

Neonatal Opiate Withdrawal !!navigator!!

Opiate agonists, including morphine and methadone, have been used to manage manifestations of opiate abstinence syndrome (i.e., postnatal withdrawal) in neonates exposed to opiates in utero.350,352,353,355,357,358,359,360 Opiates are recommended as first-line pharmacologic therapy when environmental and supportive measures (e.g., minimization of external stimuli, maximization of mother-infant contact [e.g., parental “rooming in”], breast-feeding when not contraindicated, swaddling and gentle handling) are inadequate.350,352,353,355,357,359 Other adjunctive therapy (e.g., clonidine, phenobarbital) may be added if the response to opiates is inadequate, or phenobarbital may be added if the neonate was exposed to additional substances in utero.350,352,353,355,357,358,359,365,368 Approximately 60-80% of neonates with opiate abstinence syndrome may require pharmacologic treatment for withdrawal symptoms.352,359 While morphine has been used more extensively than other opiates in the management of neonatal opiate abstinence syndrome,352,357,359,360 some studies suggest that use of methadone or buprenorphine (an opiate partial agonist) may be associated with shorter treatment durations and hospital stays compared with morphine use.360,361,362,363 However, additional study is needed to establish optimal dosage schedules and preferred opiate drugs and to evaluate longer-term (e.g., neurodevelopmental) outcomes.351,353,354,355,360

Use of standardized protocols for identification, evaluation, and treatment of neonatal opiate abstinence syndrome is recommended since use of such protocols has been shown to improve overall response, including shorter hospital stays and durations of pharmacologic treatment.350,352,353,358,359 Some evidence suggests that use of a standardized protocol may be more important than use of a specific opiate agonist (e.g., methadone versus morphine) in improving outcomes.352,359,363 Protocols generally utilize assessment tools that were developed to quantify severity of withdrawal in term neonates to facilitate decisions regarding initiation, titration, and tapering of therapy.352,353,355,357,359 (See Oral Dosage for Neonatal Opiate Withdrawal under Dosage and Administration: Dosage, in Morphine Sulfate 28:08.08 and also see Neonatal Opiate Withdrawal under Dosage and Administration: Dosage, in Methadone Hydrochloride 28:08.08.)

Dosage and Administration

[Section Outline]

Administration !!navigator!!

Opiate agonists may be administered orally, rectally, IM, subcutaneously, or IV. The parenteral route is usually used for relief of severe pain, and for relief of surgical or postoperative pain and pain during labor. IV administration is used to relieve acute, unbearable pain, and as a supplement to anesthesia. The drugs should also be administered IV in patients with shock or hypothermia in whom absorption is likely to be delayed following subcutaneous or IM injection. If opiate agonists are administered IV, usual dosage should generally be reduced and the solution should be injected slowly. An opiate antagonist and facilities for administration of oxygen and control of respiration should be immediately available during and immediately following IV administration of opiate agonists. A preservative-free preparation of morphine sulfate may also be administered epidurally or intrathecally. Morphine sulfate extended-release liposomal injection is administered epidurally. Fentanyl also may be administered percutaneously (by topical application of a transdermal system or iontophoretic transdermal system) or transmucosally (intrabuccally, sublingually, intranasally).

When therapy with an extended-release or long-acting opiate formulation is initiated, all other around-the-clock opiate analgesics should be discontinued.262 Oral extended-release tablets or capsules should be swallowed whole, one at a time, with enough water to ensure complete swallowing of the tablet or capsule immediately after it is placed in the mouth; crushing, chewing, or dissolving the capsules or tablets will result in uncontrolled delivery of the opiate agonist and can result in overdosage and death.262

Dosage !!navigator!!

Current principles of pain management indicate that opiate analgesics should be used in conjunction with appropriate nonopiate pharmacologic therapy and/or nonpharmacologic modalities in the symptomatic treatment of both acute and chronic pain.411,412,413,422,429,430,431,432 Because of the potential harms associated with opiate therapy, care is required to prevent inappropriate transition from short-term therapy for acute pain to chronic opiate therapy when other treatment modalities may be more appropriate.411,431,434 The lowest effective dosage and shortest duration of therapy consistent with treatment goals of the patient should be employed.411,413,431,432,435 Dosage of opiate agonists must be carefully adjusted according to the severity of pain and the response of the patient. Standard pain assessment tools adjusted to the patient's age and cognitive development may be employed to help the patient communicate pain intensity and to guide treatment.168 During long-term therapy of chronic noncancer pain, both pain intensity and functional status should be assessed regularly using validated tools, and progress toward therapeutic goals, adherence to the treatment plan, and presence of adverse effects should be monitored; when opiate therapy fails to provide clinically meaningful improvements in pain and functional status or when the risks of such therapy outweigh the benefits, other treatment approaches should be optimized and opiate analgesic therapy should be tapered and discontinued.411,412,413,415,423,431 Reduced dosage is indicated in poor-risk patients, in patients with substantial hepatic impairment, in patients with renal impairment, 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 (See Drug Interactions: Benzodiazepines and Other CNS Depressants.) Following parenteral administration, adverse effects such as nausea, vomiting, dizziness, and hypotension may be alleviated by maintaining the patient in a supine position and elevating his legs. In surgical patients, dosage of opiate agonists should be based on response of the patient, premedication or concomitant medication, the anesthetics which are being used, and the nature and duration of the operation.

The following doses administered orally or IM provide analgesia comparable to that produced by 30 mg of oral morphine sulfate or 10 mg of IM morphine sulfate:

Table 1. Comparative Opiate Agonist Dosage with Oral or Parenteral Administration

Equianalgesic Dose (in mg)a

Opiate Agonist

Oral

IMb

Morphine

30

10

Hydrocodone

30

-

Hydromorphone

7.5

1.5

Oxycodone

20

-

Methadone

20 (acute)

10 (acute)

Levorphanol

4 (acute)

1 (chronic)

2 (acute)

1 (chronic)

Fentanyl

-

0.1

Oxymorphone

10

1

Meperidine

300

75

aFor specific dosages for these opiate agonists, see the individual monographs in 28:08.08.

bThese are standard IM doses for acute pain in adults and also can be used to convert doses for IV infusions and repeated small IV doses (“boluses”). For single IV doses (“boluses”), use half the IM dose.

These equivalencies were based principally on single-dose studies comparing oral and IM doses of these drugs in cancer patients and patients with postoperative pain.168 When such comparisons are used to convert patients already receiving opiate therapy to therapy using a different opiate agonist or a different administration route, the equianalgesic dosage estimate should be adjusted based on consideration of the clinical situation (e.g., response to the previous regimen, adverse effects) and characteristics of the specific drugs involved (e.g., elimination half-life).168 In patients receiving chronic opiate therapy, the calculated equianalgesic dosage of the new opiate agonist generally should be reduced by about 25-50% in order to avoid inadvertent overdosage.410,412 Equivalencies based on single-dose studies may overestimate dosage requirements for methadone during chronic therapy; such comparisons should not be used to convert patients already receiving chronic opiate therapy to therapy with methadone.184,412 For further information about transferring patients from another opiate agonist to therapy with methadone, see Dosage and Administration in Methadone Hydrochloride 28:08.08.

Orally administered oxycodone in a dose of 4.88 mg produces analgesia comparable to 30 mg of oral codeine. Orally administered oxycodone also has been described as being 7-9.5 times as potent as oral codeine.160 Oxycodone hydrochloride extended-release tablets are reported to be 1.5-2 times as potent as morphine sulfate extended-release tablets (MS Contin®).160

When repeated increases in dosage are required, potential causes should be evaluated and the relative benefits and risks reassessed.412,413 Use of higher dosages requires particular caution,410,412,415 including more frequent and intensive monitoring or consultation with or referral to a pain management specialist.411,412,413 (See Chronic Noncancer Pain under Pain: Chronic Pain, in Uses.) The US Centers for Disease Control and Prevention (CDC) guideline for primary care clinicians who prescribe opiates for chronic noncancer pain states that clinicians should carefully reassess individual benefits and risks before prescribing dosages equivalent to 50 mg or more of morphine sulfate daily and should avoid dosages equivalent to 90 mg or more of morphine sulfate daily or carefully justify their decision to titrate dosage to such levels.411 Other experts have stated that a pain management specialist should be consulted before exceeding an opiate dosage equivalent to 80-120 mg of morphine sulfate daily.423,431 In contrast, guidelines developed several years earlier tended to suggest higher dosage thresholds (e.g., equivalent to 200 mg or more of morphine sulfate daily) for more frequent and intensive monitoring or consultation or referral.410,412,413 Clinicians should be aware that some states have established dosage thresholds for opiate prescribing (e.g., maximum daily dosages that can be prescribed, dosage thresholds at which consultation with a specialist is mandated or recommended)411,420,421,423 or have mandated certain risk-management strategies (e.g., review of state prescription drug monitoring program [PDMP] data prior to prescribing).411,419,423

Extended-release and Long-acting Formulations for the Management of Chronic Pain

Appropriate dosage selection and titration are essential to reduce the risk of respiratory depression associated with use of extended-release or long-acting formulations of opiate analgesics.262 The initial dosage must be individualized, taking into account the patient's prior analgesic use and risk factors for addiction, abuse, and misuse.262 Patients should be monitored closely for respiratory depression, especially during the first 24-72 hours of therapy and following any increase in dosage.262 Use of higher than recommended initial dosages in patients who are not opiate tolerant may result in fatal respiratory depression.262 Some extended-release or long-acting preparations or dosage strengths should be used only in opiate-tolerant patients.260,264,267 In patients who are being transferred from other oral opiates to therapy with an extended-release or long-acting opiate analgesic, all other around-the-clock opiate analgesics should be discontinued when therapy with the extended-release or long-acting formulation is initiated.262 Dosage must be carefully individualized since overestimation of the initial dosage in opiate-tolerant patients can result in fatal overdosage with the first dose.262 Because there is substantial interpatient variability in the relative potency of opiate analgesics and 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.262 For recommended initial dosages and titration schedules, see the individual monographs in 28:08.08.

Extended-release and long-acting formulations should be prescribed only by clinicians who are knowledgeable in the use of potent opiates for the management of chronic pain.262 Following transfer from other opiate analgesics to an extended-release or long-acting opiate analgesic, patients should be monitored for manifestations of opiate withdrawal and for oversedation or toxicity.262 Particularly close monitoring is required when patients are switched from methadone, since conversion ratios between methadone and other opiate analgesics vary widely depending on extent of prior methadone exposure and because methadone has a long half-life and tends to accumulate in plasma.262 Dosage of the extended-release or long-acting opiate agonist should be titrated to a level that provides adequate analgesia with minimal adverse effects.262 Patients should be reevaluated continually for adequacy of pain control and for adverse effects, as well as for the development of addiction, abuse, or misuse.262 Patients who experience breakthrough pain may require an increase in dosage of the extended-release or long-acting opiate agonist or “rescue” therapy with an appropriate dose of an immediate-release analgesic.262 If the pain intensity increases after dosage stabilization, an attempt should be made to identify the source of increased pain before increasing the dosage.262 Frequent communication is important among the prescriber, other members of the healthcare team, the patient, and the patient's caregiver or family during periods of changing analgesic requirements, including the initial dosage titration period.262 During long-term therapy, the continued need for opiate analgesics should be continually reevaluated.262

Cautions

[Section Outline]

Respiratory depression and, to a lesser degree, circulatory depression (including orthostatic hypotension) are the chief hazards of opiate agonist therapy. Respiratory arrest, shock, and cardiac arrest have occurred. Rapid IV administration of opiate agonists increases the incidence of these serious adverse effects.

Respiratory Depression !!navigator!!

Respiratory depression is produced even with therapeutic analgesic doses of opiate agonists, but it is usually not clinically important in patients with normal respiratory capacity. It is probable that equianalgesic doses of individual opiate agonists produce similar degrees of respiratory depression; they may differ in the duration of the depressant effects they produce. Since opiate agonists may depress deep breathing and the reflex to sigh, these drugs may induce atelectasis, especially in patients with pulmonary disorders. If opiate agonists are necessary for the relief of severe pain in these patients, breathing exercises or use of forced deep inspiration with bag and mask should be encouraged. Neonates should be observed closely for signs of respiratory depression if the mother has received opiate agonists during labor.

Modified-release (e.g., extended-release) opiate agonists are associated with a greater risk of overdose and death because of the larger amount of drug contained in each dosage unit.262 Serious, life-threatening, or fatal respiratory depression has been reported even when these formulations were used as recommended.262 Although respiratory depression can occur at any time during therapy, the risk is greatest during initiation of therapy or following an increase in dosage.262

Nervous System Effects !!navigator!!

Adverse CNS effects of opiate agonists include dizziness, visual disturbances, mental clouding or depression, sedation, coma, euphoria, dysphoria, weakness, faintness, agitation, restlessness, nervousness, seizures, and, rarely, delirium and insomnia. Opiate agonists may interfere with evaluation of CNS function, especially relative to consciousness levels, pupillary changes, and respiratory depression, thereby masking the patient's clinical course. Ambulatory patients and those patients not experiencing severe pain seem to have a higher incidence of adverse effects such as dizziness, nausea, vomiting, and hypotension than those who are in a supine position or who have severe pain. Patients with reduced blood volume, as may occur with hemorrhage or hemorrhagic shock, may be more sensitive than other patients to the hypotensive effect of opiate agonists. Although controlled studies are lacking, patients with hyperthyroidism appear to be more tolerant to the depressant effects of opiate agonists than patients with normal thyroid function.

GI Effects !!navigator!!

Adverse GI effects of opiate agonists include nausea, vomiting, and constipation. The use of morphine and its congeners in patients with chronic ulcerative colitis may stimulate motility in the colon; in patients with acute ulcerative colitis, toxic dilation may occur. Opiate agonist-induced increase in intraluminal pressure may endanger surgical anastomosis. Opiate agonists may obscure the diagnosis or clinical course in patients with acute abdominal conditions.

Opiate agonist-induced increase in biliary tract pressure may result in biliary spasm or colic, especially in the sphincter of Oddi. This spasm is usually accompanied by increased plasma concentrations of amylase and lipase. Because of this effect, plasma amylase and lipase determinations should not be performed within 24 hours after an opiate agonist has been given.

Cardiovascular Effects !!navigator!!

Several cases of QT-interval prolongation and severe cardiac arrhythmias, including torsades de pointes, have been reported during postmarketing surveillance of levomethadyl acetate hydrochloride (no longer commercially available in the US) and also have been reported in patients receiving methadone hydrochloride, especially in individuals receiving higher dosages.184,185,186 QT-interval prolongation also has been observed in healthy individuals receiving oliceridine or extended-release hydrocodone bitartrate.274,284 (For further information, see the individual monographs for Methadone Hydrochloride, Hydrocodone Bitartrate, and Oliceridine Fumarate in 28:08.08.) In addition, cardiac arrest, ST segment elevation, ventricular tachycardia, myocardial infarction, angina pectoris, and syncope have been reported during postmarketing surveillance of levomethadyl acetate hydrochloride.144 In a study evaluating safety, tolerability, and electrocardiographic (ECG) effects of propoxyphene (no longer commercially available in the US) in healthy individuals, QT-interval prolongation, widening of the QRS complex, and prolongation of the PR interval were observed at therapeutic dosages of the drug.232,233

Genitourinary and Endocrine Effects !!navigator!!

Opiate agonists may cause urinary retention and oliguria. Patients with prostatic hypertrophy or urethral stricture may be more prone to these effects. Opiate agonists may increase the risk of water intoxication in postoperative patients because of stimulation of the release of vasopressin.

Opiate agonists inhibit release of corticotropin as reflected by a decrease in plasma and urinary concentrations of 17-hydroxysteroids and 17-ketosteroids; rarely, secondary adrenocortical hypofunction or adrenal hypertrophy associated with hyperplasia of the reticular zone may follow chronic opiate agonist therapy. Onset of adrenal insufficiency in patients receiving opiate agonists or opiate partial agonists generally has occurred after at least 1 month of opiate agonist or partial agonist use, although the time to onset has ranged from within 1 day to more than 1 year.400 Manifestations of adrenal insufficiency are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.400 In many of the reported cases, patients required hospitalization.400 If adrenal insufficiency is suspected, appropriate laboratory testing should be performed promptly and physiologic (replacement) dosages of corticosteroids provided; therapy with the opiate agonist or partial agonist should be tapered and discontinued to allow recovery of adrenal function.400 If the opiate agonist or partial agonist can be discontinued, follow-up assessment of adrenal function should be performed to determine if corticosteroid replacement therapy can be discontinued.400 In some patients, switching to a different opiate improved symptoms.400

Hypogonadism and androgen deficiency have been reported in patients receiving long-term opiate agonist or opiate partial agonist therapy,400,401,402,403,404 although a causal relationship has not been established.400 Suppression of gonadotropic function produced by opiate agonists may cause impotence and a decline in libido, possibly accompanied by decreased plasma and urinary concentrations of 17-ketosteroids. Patients receiving long-term opiate agonist or partial agonist therapy who present with manifestations of hypogonadism (e.g., decreased libido, impotence, erectile dysfunction, amenorrhea, infertility) should undergo laboratory evaluation.400

Cholinergic Effects !!navigator!!

Bradycardia and other cholinergic effects which may occur following administration of opiate agonists may be controlled with atropine. In contrast to cholinergic effects produced by other opiates, meperidine or its congeners may produce anticholinergic effects such as dry mouth, palpitation, and tachycardia; uncoordinated jerky movements, muscle tremors and twitches, delirium with disorientation, hallucinations, and, occasionally, tonic-clonic (grand mal) seizures may also occur.

Other Adverse Effects !!navigator!!

Opiate agonists can release histamine (see Pharmacology: Effects on Histamine) and may produce sweating, flushing, or warmness of the face, neck, and upper thorax; pruritus; and urticaria. True anaphylactic reactions are extremely rare. Wheals, phlebitis, and pain may occur at the site of injection and local tissue irritation and induration are common following repeated subcutaneous administration of some opiate agonists. Reversible thrombocytopenia has been reported in an opiate-dependent patient with underlying chronic hepatitis who was receiving methadone.

Precautions and Contraindications !!navigator!!

Concomitant use of opiate agonists and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiate agonists, alcohol) may result in profound sedation, respiratory depression, coma, and death.416,417,418,700,701,702,703,704 Concomitant use of opiate analgesics and benzodiazepines or other CNS depressants should be reserved for patients in whom alternative treatment options are inadequate; the lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.700,703 Opiate antitussives should be avoided in patients receiving CNS depressants.700,704 Patients receiving opiate agonists and/or their caregivers should be apprised of the risks associated with concomitant therapeutic or illicit use of benzodiazepines, alcohol, or other CNS depressants.700,703 Concomitant use with alcohol should be avoided.700 (See Drug Interactions: Benzodiazepines and Other CNS Depressants.)

Because the morbidity and mortality associated with untreated opiate addiction (opiate use disorder [OUD]) can outweigh the serious risks associated with concomitant use of opiates and benzodiazepines or other CNS depressants, FDA states that therapy with opiate agonists or partial agonists (e.g., methadone, buprenorphine) for opiate addiction (i.e., medication-assisted treatment [MAT]) should not be withheld from patients receiving benzodiazepines or other CNS depressants.706 These drugs should be tapered and discontinued, if possible, in patients receiving MAT.706 However, excluding or discharging patients from MAT because of benzodiazepine or CNS depressant use is not likely to prevent such concomitant use and may lead to use outside the treatment setting, which could result in more severe outcomes.706 Careful management can reduce the risks associated with such concomitant use.706 (See Cautions in Methadone Hydrochloride 28:08.08.)

Because exposure to opiate agonists may be increased in patients with renal or hepatic impairment, use of conservative initial dosages followed by slow dosage titration generally is recommended; patients should be monitored closely for respiratory and CNS depression, particularly during dosage titration.263,264,265,267,268,269,271,272,274,275,276

Opiate agonists also should be used with caution in cachectic, debilitated, or geriatric patients, since pharmacokinetics of the drugs may be altered and these patients may be at increased risk for respiratory depression.260,263,264,265,267,268,269,271,272,273,274,275,276 These patients should be monitored closely, particularly during initiation of therapy and dosage titration and when other drugs with respiratory depressant effects are used concomitantly.260,263,264,267,268,272,274,275,276

Opiate agonists are contraindicated in patients with substantial respiratory depression or with acute or severe bronchial asthma or hypercarbia in unmonitored settings or in the absence of resuscitative equipment.260,263,264,265,267,268,269,271,272,273,274,275,276 Opiate agonists should be used with extreme caution in patients with preexisting respiratory depression and in those with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve, such as asthma, chronic obstructive pulmonary disease, cor pulmonale, severe obesity, sleep apnea, myxedema, kyphoscoliosis, CNS depression, or coma.260,263,264,265,266,267,268,269,271,272,273,274,275,276 In such patients, even therapeutic doses of opiate agonists may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea.260,263,264,265,266,267,268,269,271,272,273,274,275,276 Alternative analgesics without opiate agonist activity should be considered, and opiate agonists should be used only with close monitoring and at the lowest effective dosage in such patients.260,263,264,265,267,268,269,271,272,273,274,275,276 The risk of respiratory depression also is increased in geriatric, cachectic, or debilitated patients; following large initial doses of opiate agonists in patients who are not opiate tolerant; and in patients receiving other agents with respiratory depressant effects.260,263,264,265,266,267,268,269,271,272,273,274,275,276

Clinicians should routinely discuss the availability of the opiate antagonist naloxone with all patients receiving new or reauthorized opiate prescriptions for pain management or new or reauthorized prescriptions for medications for treatment of OUD.750 Clinicians should consider prescribing naloxone for patients receiving opiate analgesics who are at increased risk of opiate overdosage (e.g., those receiving concomitant therapy with benzodiazepines or other CNS depressants, those with a history of opiate or substance use disorder, those with medical conditions that could increase sensitivity to opiate effects, those who have experienced a prior opiate overdose) and should strongly consider prescribing naloxone for all patients receiving medications for treatment of OUD.411,431,750 Clinicians also should consider prescribing naloxone when patients receiving opiates for pain management or for treatment of OUD have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.750 Even if patients are not receiving an opiate for pain management or medication for treatment of OUD, a naloxone prescription should be considered if the patient is at increased risk of opiate overdosage (e.g., those with a current or past diagnosis of OUD, those who have experienced a prior opiate overdose).750 (See Naloxone Hydrochloride 28:10.)

Opiate agonists may cause severe hypotension in patients whose ability to maintain blood pressure has been compromised by blood volume depletion or concomitant use of certain drugs (e.g., general anesthetics, phenothiazines). Because opiate agonists may cause vasodilation that can further reduce cardiac output and blood pressure in patients with circulatory shock, the drugs should be used with caution in these patients; use of extended-release opiate agonists generally should be avoided in such patients.260,264,265,268,269,271,272,273,274,275,276 Opiate agonists may cause orthostatic hypotension and syncope in ambulatory patients.260,263,264,267,268,269,271,272,273,274,275,276

The respiratory depressant effects of opiate agonists promote carbon dioxide retention, which results in elevation of intracranial pressure.260,263,264,265,267,268,269,271,273,274,275,276 The ability of opiate agonists to increase intracranial pressure may be markedly exaggerated in patients with head injury, other intracranial lesions, or preexisting elevated intracranial pressure.265,269,271,272,273,274 Opiate agonists also produce effects (e.g., pupillary changes, altered consciousness) that may obscure the clinical course and neurologic signs of further increases in intracranial pressure in patients with head injuries.260,263,264,265,266,267,268,269,271,272,273,274,275,276 Patients who may be particularly susceptible to the effects of carbon dioxide retention (e.g., those with elevated intracranial pressure, brain tumors, or impaired consciousness or coma) should be monitored closely.260,263,264,265,266,267,268,274,275,276 Use of long-acting or extended-release opiate agonists generally should be avoided in patients with impaired consciousness or coma.260,263,264,267,268,274,275,276

Serotonin syndrome has been reported during concomitant use of opiate agonists and serotonergic drugs at recommended dosages.400 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.400 (See Drug Interactions: Drugs Associated with Serotonin Syndrome.)

Opiate agonists are contraindicated in patients with known or suspected paralytic ileus and GI obstruction.260,263,264,265,267,268,269,271,272,273,274,275,276 Opiate agonists should be used with caution in patients at risk for ileus.271 Because opiate agonists diminish propulsive peristaltic waves in the GI tract and decrease bowel motility, postoperative patients receiving opiate analgesia should be monitored for decreased bowel motility.264,265,272,273,274 Chronic use of opiate agonists may result in obstructive bowel disease, especially in patients with underlying intestinal motility disorders.269 Opiate agonists may cause or aggravate constipation.269 Opiate agonists may obscure the diagnosis or clinical course of patients with acute abdominal conditions.264,265,269,271,272,273,274 Because opiate agonists may cause spasm of the sphincter of Oddi and diminish biliary and pancreatic secretions, patients with biliary tract disease, including those with acute pancreatitis, should be monitored for worsening symptoms.260,263,264,265,267,268,269,271,272,273,274,275,276

Because of their cholinergic effects, opiate agonists should be used with caution in patients with cardiac arrhythmias.

Opiate agonists may aggravate preexisting seizures in patients with seizure disorders and may induce or aggravate seizures in some clinical settings.260,263,264,265,268,269,271,273,275,276 During long-term opiate agonist therapy, patients with seizure disorders should be monitored for worsening of seizure control.260,263,264,268,275,276

Opiate agonists also should be used with caution in patients with hypothyroidism, adrenocortical insufficiency (e.g., Addison's disease), prostatic hyperplasia or urethral stricture, toxic psychosis, acute alcoholism, or delirium tremens.265,269,271,273

Individuals who perform hazardous tasks requiring mental alertness or physical coordination should be warned about possible adverse CNS effects of opiate agonists.

Patients who are unable to tolerate one agent may be able to tolerate a different agent. Opiate agonists are contraindicated in patients with known hypersensitivity to the particular drug.

Pediatric Precautions !!navigator!!

Serious adverse events, including deaths, have been reported in pediatric patients receiving codeine or tramadol for management of pain; in some of these cases, ultrarapid or extensive metabolism of cytochrome P-450 (CYP) isoenzyme 2D6 substrates was confirmed or suspected.249,250,251,252,253,254,705 (See Pharmacogenomics under Pharmacokinetics: Elimination.) Because of the potential for serious or fatal adverse effects in pediatric patients, use of codeine or tramadol for the management of pain is contraindicated in children younger than 12 years of a tramadol and codeine also are contraindicated in pediatric patients younger than 18 years of age for the management of postoperative pain following tonsillectomy and/or adenoidectomy.249,250,251,255,705 FDA also states that use of codeine or tramadol for pain management is not recommended in children 12-18 years of age who are obese or have conditions such as obstructive sleep apnea or compromised respiratory function, since they may be susceptible to the respiratory depressant effects of the drug.705 (See Codeine 28:08.08 and Tramadol Hydrochloride 28:08.08.)

Serious adverse events, including deaths, also have been reported in pediatric patients receiving opiate agonists for the management of cough and cold.705,710 For information on precautions and contraindications associated with use of codeine or hydrocodone as antitussives in pediatric patients, see Cautions: Pediatric Precautions, in Codeine 48:08 and in Hydrocodone Bitartrate 48:08.

Geriatric Precautions !!navigator!!

Geriatric patients are more likely than younger individuals to experience adverse effects, especially respiratory depressant effects, of opiate agonists and may be more sensitive to the analgesic effects of these drugs.176,177 Geriatric adults also are more likely to have prostatic hyperplasia or obstruction and renal impairment and thus may be at increased risk of opiate agonist-induced urinary retention.176 Clearance of opiate agonists may be decreased in geriatric patients, resulting in longer durations of action.176,178 Care should be exercised, and appropriate dosage adjustments (e.g., lower initial doses, longer dosing intervals) should be considered.168,176,177,178

Some clinicians recommend that methadone and other opiate agonists with long elimination half-lives be used with caution in geriatric patients because of the greater frequency of decreased renal and hepatic function observed in these individuals.168,177 Meperidine should be used with caution in geriatric patients, and dosage adjustment should be considered because of the potential for adverse CNS effects (e.g., anxiety, excitation, tremors, myoclonus, seizures) secondary to accumulation of the toxic metabolite normeperidine, especially in those with decreased renal and hepatic function.118,168,179 Because of this risk, many experts recommend that alternative opiates be used in patients with renal impairment and in other individuals requiring large or repeated doses of opiate agonists.180,181

Pregnancy and Lactation !!navigator!!

Pregnancy

Analysis of data from the National Birth Defects Prevention Study, a large population-based, case-control study, suggests that therapeutic maternal use of opiate agonists during the period of organogenesis is associated with a low absolute risk of birth defects, including heart defects, spina bifida, and gastroschisis.257,258 Although there are no adequate and controlled studies to date in humans, some opiate agonists (e.g., morphine) have been shown to be teratogenic in animals.260 Therefore, opiate agonists should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Prolonged maternal use of opiate agonists during pregnancy can result in neonatal opiate withdrawal syndrome with manifestations of irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, and failure to gain weight.259,260,261 In contrast to adults, the withdrawal syndrome in neonates may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts.259,260,261 Women who require prolonged opiate agonist therapy during pregnancy should be advised of the risk of neonatal opiate withdrawal syndrome, and availability of appropriate treatment should be ensured.259,260,261 The onset, duration, and severity of the syndrome vary depending on the specific opiate agonist used, duration of use, timing and amount of last maternal use, and rate of drug elimination by the neonate.259,260,261 Use of standardized protocols for identification and management of opiate withdrawal syndrome has been shown to improve overall response, including reductions in hospital stay and duration of pharmacologic treatment.350,352,359 When environmental and supportive measures are inadequate, opiates are recommended as first-line pharmacologic therapy.352,357,359 (See Uses: Neonatal Opiate Withdrawal.)

Use of opiate agonists during late pregnancy can result in neonatal respiratory depression.257

Use of long-acting or extended-release opiate agonist analgesics is not recommended immediately before or during labor, when shorter-acting analgesics or other analgesic techniques may be more appropriate.259,260,261 Opiate agonists may prolong labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions.259,260,261 However, this effect is inconsistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.259,260,261

Lactation

Higher than expected concentrations of morphine (the active metabolite of codeine) may be distributed into breast milk of women taking codeine who are ultrarapid metabolizers of CYP2D6 substrates.205,206,207,214 (See Pharmacogenomics under Pharmacokinetics: Elimination.) Because of the potential for serious adverse effects in nursing infants, especially if the infant's mother is an ultrarapid metabolizer of CYP2D6 substrates, use of codeine is not recommended in nursing women.205,206,207,214,705 (See Codeine 48:08 and also see Codeine 28:08.08.) Because tramadol is distributed into milk and has similar risks as codeine in ultrarapid metabolizers of CYP2D6 substrates, use of tramadol also is not recommended in nursing women.705 (See Cautions in Tramadol Hydrochloride 28:08.08.)

Drug Interactions

[Section Outline]

Benzodiazepines and Other CNS Depressants !!navigator!!

Concomitant use of opiate agonists and benzodiazepines or other CNS depressants including other opiate agonists, anxiolytics, general anesthetics, tranquilizers, sedatives, hypnotics, muscle relaxants, antipsychotics, and alcohol can increase the risk of respiratory depression, hypotension, profound sedation, coma, and death.260,263,264,265,267,268,269,271,272,273,275,700,701,702,703,704 Opiate analgesics frequently are implicated as contributing to fatal overdoses involving other CNS depressants, and epidemiologic studies have shown that a substantial proportion of fatal opiate overdoses involve the concurrent use of benzodiazepines, alcohol, or other CNS depressants.416,417,418,435,700,701,702

Whenever possible, concomitant use of opiate agonists and benzodiazepines should be avoided.410,411,415,435 Alcohol also should be avoided in patients receiving opiate agonists.700,700,704 Concomitant use of opiate analgesics and benzodiazepines or other CNS depressants should be reserved for patients in whom alternative treatment options are inadequate, and opiate antitussive agents should be avoided in patients receiving CNS depressant therapy.700,703 If a decision is made to prescribe opiate analgesics and CNS depressants concomitantly, the lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for sedation, hypotension, and respiratory depressant effects.260,263,264,265,267,268,269,271,272,273,275,700,703 If a benzodiazepine or other CNS depressant is required for any indication other than epilepsy in a patient receiving opiate therapy for analgesia, the drug should be initiated at a lower dosage than indicated in the absence of opiate therapy and titrated based on clinical response.700,703 In patients receiving a CNS depressant, opiate analgesics, if required, should be initiated at a reduced dosage and titrated based on clinical response.700,703

Because the morbidity and mortality associated with untreated opiate addiction can outweigh the serious risks associated with concomitant use of opiates and benzodiazepines or other CNS depressants, FDA states that therapy with opiates (e.g., methadone) for opiate addiction (i.e., medication-assisted treatment [MAT]) should not be withheld from patients receiving benzodiazepines or other CNS depressants.706 Clinicians should develop treatment plans that minimize the risks associated with such concomitant use.706 If possible, benzodiazepines or other CNS depressants should be tapered and discontinued.706 (See Cautions in Methadone Hydrochloride 28:08.08.)

Clinicians should consider prescribing the opiate antagonist naloxone for patients receiving opiates who are at increased risk of opiate overdosage, including those receiving benzodiazepines or other CNS depressants concomitantly.411,431,750 (See Cautions: Precautions and Contraindications.)

When considering use of extended-release or long-acting opiate agonist therapy in a patient already receiving another CNS depressant, the duration of use and response to the CNS depressant, including the degree of tolerance to CNS depressant effects, as well as the patient's use of alcohol or any illicit CNS depressants, should be evaluated.260,263,264,267,268,272,275 Concomitant use of alcohol with some oral extended-release opiate agonist formulations can result in increased plasma concentrations of the opiate agonist and potentially fatal overdosage.260,264,275

Antidepressants !!navigator!!

Opiate agonists may potentiate the effects of tricyclic antidepressants and monoamine oxidase (MAO) inhibitors, including procarbazine hydrochloride; therefore, opiate agonists should be used with great caution and in reduced dosage when used in conjunction with such drugs. Virtually all the reported incidents of opiate agonist interaction with MAO inhibitors have occurred in patients receiving meperidine. (See Meperidine Hydrochloride 28:08.08.) Because MAO inhibitors may potentiate the effects of opiate agonists and because these effects may be severe and unpredictable, use of opiate agonists during or within 14 days following treatment with an MAO inhibitor is not recommended.260,264,265,266,267,269,271,272 Meperidine is contraindicated in patients receiving MAO inhibitors. Some manufacturers state that if an opiate agonist is required in patients receiving MAO inhibitors, a sensitivity test should be performed with small increments of morphine or the opiate agonist administered over a period of several hours while the patient is kept under close medical observation.

Drugs Associated with Serotonin Syndrome !!navigator!!

Serotonin syndrome may occur in patients receiving opiate agonists in conjunction with other serotonergic drugs,145,146,147,148,150,270,277,400 including serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists (“triptans”), selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants, antiemetics that are 5-HT3 receptor antagonists, buspirone, cyclobenzaprine, dextromethorphan, lithium, St. John's wort ( Hypericum perforatum ), tryptophan, other serotonin modulators (e.g., mirtazapine, nefazodone, trazodone, vilazodone), and MAO inhibitors (both those used to treat psychiatric disorders and others, such as linezolid, methylene blue, and selegiline).400 Serotonin syndrome may occur within the recommended dosage ranges for these drugs.400 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.400

If concurrent therapy with opiate agonists and serotonergic drugs is warranted, patients should be monitored for serotonin syndrome, particularly during initiation of therapy and dosage increases.400 If serotonin syndrome is suspected, treatment with opiate agonists and any concurrently administered serotonergic agents should be discontinued.400

For further information on serotonin syndrome, including manifestations and treatment, see Drug Interactions: Serotonergic Drugs, in Fluoxetine Hydrochloride 28:16.04.20.

Opiate Antagonists and Opiate Partial Agonists !!navigator!!

Withdrawal symptoms may occur in patients receiving opiate agonists concomitantly with opiate antagonists (e.g., naloxone, naltrexone) or opiate partial agonists (e.g., buprenorphine, butorphanol, nalbuphine, pentazocine).184 Partial agonists should not be administered in patients receiving opiate agonists as they may reduce the analgesic effect and/or precipitate withdrawal symptoms.184

Drugs Affecting Hepatic Microsomal Enzymes !!navigator!!

Metabolism of some opiates (e.g., codeine, fentanyl, hydrocodone, methadone, oliceridine, oxycodone, tramadol) is mediated by the cytochrome P-450 (CYP) microsomal enzyme system.184,187,188,189,216,263,264,266,267,268,269,270,284 Metabolism of methadone is mediated mainly by CYP isoenzymes 2B6, 2C19, and 3A4, and, to a lesser extent, by CYP isoenzymes 2C9 and 2D6.263 Fentanyl, hydrocodone, and oxycodone are metabolized mainly by CYP3A4, although CYP2D6 also is involved in the metabolism of hydrocodone and oxycodone.264,266,267,268 Codeine and tramadol are metabolized by CYP2D6 and CYP3A4.269,270 Oliceridine also is metabolized mainly by CYP2D6 and CYP3A4, with minor contributions from CYP2C9 and CYP2C19.284 Concomitant use of these opiates with drugs that induce or inhibit these isoenzymes may alter metabolism and clearance of the opiate.184,187,188,216,263,264,266,267,268,269,270,284 For further information, see Drug Interactions in the individual monographs in 28:08.08.

Drugs Affecting the P-glycoprotein Transport System !!navigator!!

Some opiate agonists (e.g., hydromorphone, morphine, tapentadol) are eliminated mainly as glucuronide conjugates.260,271,276,277 Concomitant use of morphine with P-glycoprotein inhibitors has been shown to increase systemic exposure to morphine.260,276

Drugs that Prolong QT Interval !!navigator!!

Because of the potential for prolongation of the QT interval or serious cardiac arrhythmias, methadone should be used with extreme caution in patients receiving drugs that are known to prolong the QT interval or drugs that may result in electrolyte disturbances (e.g., hypokalemia, hypomagnesemia) that may prolong the QT interval.184 For further information on cardiovascular effects of methadone and associated drug interactions, see Methadone Hydrochloride 28:08.08.

Anticholinergic Agents !!navigator!!

Concomitant use of opiate agonists and drugs with anticholinergic activity may increase the risk of urinary retention or severe constipation, which can lead to paralytic ileus.260,263,264,265,267,268,269,271,272 Patients receiving such concomitant therapy should be monitored for signs or symptoms of urinary retention and reduced GI motility.260,263,264,267,268

Neuromuscular Blocking Agents !!navigator!!

Opiate agonists may enhance the neuromuscular-blocking action of skeletal muscle relaxants.

Amphetamines !!navigator!!

Dextroamphetamine may enhance opiate agonist analgesia.

Diuretics !!navigator!!

Opiate agonists may decrease the effects of diuretics by inducing the release of vasopressin (antidiuretic hormone).260,268,276

Other Information

[Section Outline]

Acute Toxicity

Manifestations !!navigator!!

Opiate agonist overdosage usually produces CNS depression ranging from stupor to a profound coma; respiratory depression which may progress to Cheyne-Stokes respiration and/or cyanosis; cold, clammy skin and/or hypothermia; flaccid skeletal muscles; bradycardia; and hypotension. In patients with severe overdosage, particularly following rapid IV administration of an opiate agonist, apnea, circulatory collapse, cardiac arrest, respiratory arrest, and death may occur. Complications such as pneumonia, shock, and/or pulmonary edema may also prove fatal. Although miosis is characteristic of overdosage with morphine derivatives and methadone, mydriasis may occur in terminal narcosis or severe hypoxia. Overdosage of meperidine or its congeners may produce mydriasis rather than miosis. Toxic effects of meperidine and its derivatives may be excitatory, especially in patients who have developed tolerance to the depressant effects of the drug. These patients may exhibit dry mouth, increased muscular activity, muscle tremors and twitches, tachycardia, delirium with disorientation, hallucinations, and, occasionally, tonic-clonic seizures.

Overdosage may be caused inadvertently by delayed absorption when repeated doses of opiate agonists are administered IM or subcutaneously to a patient with hypothermia, shock, hypotension, or any other condition that might impair circulation. When circulation is restored in these patients, large amounts of the opiate agonist are absorbed into the blood stream. Therefore, such patients should receive IV rather than subcutaneous or IM injections with the consideration that IV administration may increase the already severe cardiorespiratory impairment.

Modified-release (e.g., extended-release) opiate agonists are associated with a greater risk of overdosage and death because of the larger amount of drug contained in each dosage unit.262 Abuse or misuse of extended-release dosage forms by crushing or chewing the extended-release capsules or tablets, snorting the contents, or injecting the dissolved contents or by intentionally compromising the transdermal system (e.g., by swallowing, snorting, or injecting drug extracted from the system) will result in uncontrolled delivery of the opiate agonist and can result in overdosage and death.262,267 Inadvertent exposure to or ingestion of these formulations, especially by a child, also can result in respiratory depression and fatal overdosage.262,267

Neonates whose mothers have received opiate agonists during labor should be closely observed for signs of respiratory depression and treatment for opiate agonist overdosage should be instituted if necessary.

Treatment !!navigator!!

In the treatment of opiate agonist overdosage, especially in the presence of apnea, primary attention should be given to reestablishment of adequate respiratory exchange by maintaining an adequate, patent airway, using assisted or controlled respiration and oxygen as necessary. Opiate agonist-induced respiratory depression may be treated with naloxone hydrochloride (an opiate antagonist) (see 28:10); however, the duration of respiratory depression following overdosage of an opiate agonist may be longer than the duration of action of the opiate antagonist and other more immediate supportive and symptomatic treatment should also be initiated. In addition, it should be considered that use of an opiate antagonist in patients physically dependent on opiate agonists may precipitate an acute withdrawal syndrome that cannot be readily suppressed while the action of the antagonist persists. The safety and efficacy of naltrexone hydrochloride in the management of acute opiate toxicity have not been established. If respiratory depression is associated with muscular rigidity, administration of a neuromuscular blocking agent may be necessary to facilitate assisted or controlled respiration. Muscular rigidity may also respond to opiate antagonist therapy. Gastric lavage may be effective even many hours after drug ingestion since pylorospasm produced by the opiate agonist may cause much of the drug to be retained in the stomach for an extended period of time.

Chronic Toxicity

Opiate agonists have the potential to produce physical dependence and are subject to control under the Federal Controlled Substances Act of 1970. (See Preparations in the individual monographs.) Because of the drugs' opiate agonist activity at µ-receptors, tapentadol and tramadol also can produce dependence.100,101,102,103,104,105,106,107,108,111,112,224,226,228,229,231 The abuse potential of tapentadol is similar to that of hydromorphone, and tapentadol is subject to control under the Federal Controlled Substances Act of 1970.224,230,231 Although tramadol was not originally subject to control as a scheduled drug, current data suggest that the abuse potential of tramadol is less than that of morphine or oxycodone but similar to that of propoxyphene, and tramadol became subject to control under the Act effective August 18, 2014.256

Tolerance, psychological dependence, and physical dependence may occur in patients receiving opiate agonists. Addiction can occur at recommended dosages or may be associated with misuse or abuse.262,265 Each patient's risk for addiction, abuse, or misuse should be assessed prior to prescribing opiate analgesics and all patients receiving the drugs should be monitored regularly for the development of these behaviors or conditions.262,265,269,271 Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression).262,271 The potential for these risks should not prevent appropriate use of opiate agonists for the management of pain;262,265,269,271 however, use of the drugs in patients at increased risk necessitates intensive counseling about the risks and proper use, along with intensive monitoring for signs of addiction, abuse, and misuse.262,271

Surveillance data suggest a parallel relationship between the number of opiate analgesic prescriptions dispensed in the US and the diversion and abuse of these drugs and associated adverse outcomes.278,279 Prescriptions for opiate analgesics in the US increased substantially (nearly tripling) from 1991 to 2011, and then plateaued or decreased slightly from 2011 through 2013;278,279 rates of diversion and abuse of prescription opiate analgesics followed similar patterns.279 Deaths associated with the use of prescription opiate analgesics increased sharply from 1999 to 2006, plateaued for several years, decreased slightly through 2013, but then increased again in 2014.279,280,282,283 From 2001 to 2014, deaths associated with the use of prescription opiate analgesics increased 3.4-fold.283 Fatal overdoses of heroin (diacetylmorphine, which is not available on the legitimate commercial market) have increased since 2007, with substantial increases observed each year from 2011 through 2014.278,279,280,282,283 Fatal heroin overdoses in 2013 were nearly quadruple the rate in the early 2000s, with most of the increase occurring after 2010.278,282 From 2001 to 2014, the number of heroin-related deaths increased sixfold.283 Although data suggest that only a very small proportion of individuals who abuse prescription opiate analgesics transition to heroin use, prescription opiate abuse has emerged as a growing risk factor for heroin use.278 In a survey of individuals entering treatment programs for heroin addiction, 80% of those who began abusing opiates in the 1960s reported that heroin was their first opiate of abuse, whereas 75% of those who began abusing opiates in the 2000s reported that their first opiate of abuse was a prescription drug.278,281 Factors that have been cited as potentially contributing to the upsurge in heroin use include the lower cost and greater accessibility of high-purity heroin, the introduction of abuse-deterrent prescription formulations, and flattening of opiate prescribing rates.278,279

Tolerance to the analgesic, respiratory depressant, sedative, and euphoric effects of opiate agonists usually develops during prolonged therapy; however, overdosage even in patients who have developed tolerance will cause respiratory depression and death. Tolerance to all effects of opiate agonists does not develop uniformly. Meperidine-dependent patients, for example, receiving 3-4 g of the drug daily, do not develop substantial tolerance to the excitant and anticholinergic actions of meperidine and may develop stimulatory symptoms of acute meperidine toxicity.

Development of tolerance seems to depend on the degree of opiate agonist-induced CNS depression and the extent to which this depression is continued by frequent or prolonged opiate agonist administration and may occur as a result of prolonged medical use or intentional abuse. Development of tolerance in patients receiving meperidine has been reported to be more gradual than in those receiving morphine; tolerance to methadone may develop more slowly than to meperidine. Patients who have developed tolerance to one opiate agonist usually exhibit cross-tolerance to other opiate agonists. Cross-tolerance among opiate agonists may be incomplete (see Cautions in Methadone Hydrochloride 28:08.08).184,190

Continued administration of opiate agonists may lead to physical dependence which is closely related to tolerance. Individuals who are physically dependent on opiate agonists may remain relatively asymptomatic as long as they are able to maintain their daily opiate agonist requirement. Individuals who are morphine dependent will usually continue to exhibit miosis while those who are dependent on methadone may develop some tolerance to miosis. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug or receive an opiate antagonist. The abstinence syndrome varies in severity according to the specific drug and the amount of drug the patient has been taking. If the abstinence syndrome is precipitated by the parenteral administration of naloxone, symptoms will be apparent within a few minutes and maximal within 30 minutes after administration; effects will usually be more severe than those following withdrawal of the opiate agonist. (Induction of methadone abstinence in this manner is especially severe.) Because of naltrexone's long duration of antagonist effect, withdrawal precipitated by the drug may be prolonged. Until the antagonist has been eliminated, large doses of opiate agonists will only partially suppress these symptoms.

In patients who have taken up to 80 mg of morphine sulfate daily for up to one month, withdrawal symptoms are usually slight and require little or no treatment. A severe abstinence syndrome occurs if the patient has received 240 mg or more of morphine sulfate for 30 days or longer. Severe opiate agonist abstinence syndrome is characterized by restlessness, lacrimation, rhinorrhea, yawning, perspiration, gooseflesh, restless sleep or “yen,” and mydriasis during the first 24 hours. As the syndrome progresses, these symptoms become more severe and may be accompanied by twitching and spasms of muscles; kicking movements; severe aches in back, abdomen, and legs; abdominal and muscle cramps; hot and cold flashes; insomnia; nausea, vomiting, and diarrhea; coryza and severe sneezing; and increases in body temperature, blood pressure, respiratory rate, and heart rate. These symptoms reach peak intensity 36-72 hours following withdrawal of morphine sulfate. In addition, marked increase in urinary 17-ketosteroid concentrations and leukocytosis with leukocyte counts above 14,000/mm3 occur frequently. Because of the excessive loss of fluids through sweating, vomiting and diarrhea, there is usually marked weight loss, dehydration, ketosis, and disturbances in acid-base balance. Cardiovascular collapse may occur especially in aged or debilitated patients. Administration of an opiate agonist will readily suppress most withdrawal symptoms except those resulting from fluid deficiency. If no treatment is given, most observable symptoms disappear in 5-14 days; however, there appears to be a phase of secondary or chronic abstinence which may last for 2-6 months after withdrawal of the drug. This phase is associated with gradually decreasing insomnia, irritability, and muscular aches. In addition, the patient may have miosis and a slight lowering of blood pressure, pulse rate, and body temperature; respiratory centers exhibit a decreased response to the stimulatory effects of carbon dioxide.

In patients who are physically dependent on meperidine, abstinence symptoms usually occur 3-4 hours after the last dose of the drug, reaching maximal intensity within 8-12 hours. Although symptoms associated with meperidine withdrawal are generally milder than those of morphine withdrawal, during the period of maximal intensity, muscle twitching, restlessness and nervousness may be worse than with morphine. Symptoms of meperidine withdrawal decline until few are apparent after 4-5 days.

Because of the cumulative effects of methadone, abstinence symptoms following its withdrawal are less intense and more prolonged than those following withdrawal of other opiate agonists and may not be manifested until 3 or 4 days after the last dose. Peak intensity of symptoms occurs on the sixth day and may include weakness, anxiety, anorexia, insomnia, abdominal discomfort, headache, sweating, and hot and cold flashes. Few symptoms are apparent after 10-14 days, although patients may exhibit lethargy and anorexia for longer periods. Other opiate agonists produce abstinence syndromes similar to those described previously. In general, the shorter the onset and duration of action of the drug, the greater the intensity and rapidity of onset of withdrawal symptoms. Those drugs which are eliminated slowly produce a mild, prolonged abstinence syndrome.

In the treatment of physical dependence, the patient may be detoxified by gradual reduction of daily opiate agonist dosage. If abstinence symptoms become severe, the patient may receive methadone (see Methadone Hydrochloride 28:08.08). Temporary administration of tranquilizers and sedatives may aid in reducing patient anxiety and opiate agonist craving. Symptoms involving GI disturbance or dehydration should be treated accordingly. Supportive social, vocational, psychiatric, and educational services should be available to the patient. For some patients, maintenance treatment with relatively stable doses of methadone or buprenorphine for relatively long periods may be necessary in the management of opiate dependence. (See Methadone Hydrochloride 28:08.08 and Buprenorphine Hydrochloride 28:08.12.) Therapy with naltrexone, an opiate antagonist, may be a useful adjunct in the maintenance of opiate cessation in some individuals formerly physically dependent on opiates who have successfully undergone detoxification. (See Naltrexone Hydrochloride 28:10.)

Alternatively, rapid detoxification has been used in the management of opiate withdrawal in opiate-dependent individuals, both in inpatient and outpatient settings. Rapid opiate detoxification involves the administration of opiate antagonists such as naloxone and naltrexone to shorten the time period of detoxification. The reported advantage of this technique is to minimize the risk of relapse and to initiate maintenance therapy with naltrexone and psychosocial interventions more quickly. Ultrarapid detoxification is similar, but involves the administration of opiate antagonists while the patient is sedated or under general anesthesia. However, the risk of adverse respiratory and cardiovascular effects associated with this procedure must be considered as well as the costs of general anesthesia and hospitalization. Safety and efficacy of these therapies have not been established and further study is needed.

Neonates born to mothers physically dependent on opiate agonists may also be opiate dependent and usually exhibit withdrawal symptoms from 1-4 days after birth. These symptoms include generalized tremors and hypertonicity with any form of tactile stimuli, hyperalertness, sleeplessness, excessive crying, vomiting, diarrhea, yawning, and, occasionally, fever. (See Pregnancy under Cautions: Pregnancy and Lactation and also see Uses: Neonatal Opiate Withdrawal.)

Pharmacology

Nervous System Effects !!navigator!!

Opiate agonists exert their principal pharmacologic effect on the CNS and on the intestines. The drugs interact as agonists at specific receptor binding sites in the CNS and other tissues. Opiate receptors are present in highest concentration in the limbic system, thalamus, striatum, hypothalamus, midbrain, and spinal cord. Several subtypes of opiate receptors have been described including the µ-receptor, which is localized in pain modulating regions of the CNS; the κ-receptor, which is localized in the deep layers of the cerebral cortex; the δ-receptor, which is localized in the limbic regions of the CNS; and the σ-receptor, which is thought to mediate the dysphoric and psychotomimetic effects of some opiate partial agonists (e.g., pentazocine). Morphine, the prototype opiate agonist, has agonist activity at the µ- and κ-receptors but has little, if any, activity at the σ-receptor; the drug is a more potent agonist at the µ- than κ-receptor. Morphine may also have some agonist activity at the δ-receptor. Agonist activity at the µ- or κ-receptor can result in analgesia, miosis, and/or decreased body temperature. Agonist activity at the µ-receptor can also result in suppression of opiate withdrawal, whereas antagonist activity can result in precipitation of withdrawal. Respiratory depression may be mediated by µ-receptors, possibly µ2-receptors (which may be distinct from µ1-receptors involved in analgesia); κ- and δ-receptors may also be involved in respiratory depression. Cough-suppressant opiate receptors have also been suggested.

Opiate agonists act at several sites within the CNS involving several systems of neurotransmitters to produce analgesia, but the precise mechanism of action has not been fully elucidated. Opiate agonists do not alter the threshold or responsiveness of afferent nerve endings to noxious stimuli nor the conduction of impulses along peripheral nerves; instead, the drugs alter the perception of pain at the spinal cord and higher levels in the CNS (substantia gelatinosa, spinal trigeminal nucleus, periaqueductal gray, periventricular gray, medullary raphe nuclei, hypothalamus) and the patient's emotional response to pain.

In addition to analgesia, the effects of opiate agonists on the CNS cause suppression of the cough reflex, respiratory depression, drowsiness, sedation, change in mood, euphoria, dysphoria, mental clouding, nausea, vomiting, and EEG changes. Dosages higher than usual analgesic dosages result in anesthesia; however, prevention of awareness during and recall after opiate-agonist anesthesia may require supplementation with other agents (e.g., benzodiazepines), since awareness and recall of the surgical procedure have been reported by some patients even at high doses of an opiate agonist alone. Large doses of opiate agonists may induce excitation or seizures. Morphine and its congeners and methadone depress the cough reflex by a direct effect on the cough centers in the medulla; antitussive effects may occur with doses lower than those required for analgesia. Meperidine and its congeners generally have appreciable antitussive activity only in analgesic doses. Opiate agonists produce respiratory depression by a direct effect on the respiratory centers in the brain stem resulting in decreased sensitivity and responsiveness to increases in serum carbon dioxide tension (Pco2). These drugs depress the pontine and medullary centers which regulate respiratory rhythm and may also alter voluntary control of respiration. Depressed respiration produces an increase in arterial Pco2 resulting in cerebral vasodilation and a consequential rise in cerebral blood flow and CSF pressure. Increased CSF pressure is more likely to occur following IV administration of opiate agonists than following other routes of administration. Nausea is probably caused by stimulation of the chemoreceptor trigger zone (CTZ) in the medulla oblongata or by the occurrence of orthostatic hypotension. Vomiting may result from stimulation of the CTZ. In addition, the opiate agonists depress the vomiting center; therefore, subsequent doses of the drugs are unlikely to produce vomiting. Increase in vestibular sensitivity may also contribute to the high incidence of nausea and vomiting in ambulatory patients.

Ocular Effects !!navigator!!

Morphine and its congeners and, to a lesser extent, methadone cause miosis which is antagonized by atropine. Some reports state that meperidine and its congeners also produce miosis, whereas others indicate that these drugs tend to produce mydriasis or no pupillary change. Therapeutic doses of morphine and its congeners increase accommodation and sensitivity to light reflex and decrease intraocular tension in both normal and glaucomatous eyes. Opiate agonists decrease the response of the hypothalamus to afferent stimulation; slight hypothermia may also occur.

GI Effects !!navigator!!

Gastric, biliary, and pancreatic secretions are decreased by opiate agonists and the drugs delay digestion. Although the precise action of clinical doses of opiate agonists on GI smooth muscle tone is controversial, the ultimate result is constipation. Morphine congeners, meperidine and its congeners, and methadone are less constipating than morphine. Opiate agonists increase smooth muscle tone in the antral portion of the stomach, the small intestine (particularly the duodenum), the large intestine, and the sphincters. It has been generally believed that tone increases to the point of spasm. Although intensity and frequency of propulsive contractions are decreased, amplitude of nonpropulsive rhythmic contractions may be enhanced. Vigorous spasms that occur in the smooth muscle of intestinal walls and sphincters may be partially blocked by atropine. Although meperidine and its congeners have some anticholinergic properties, these drugs produce smooth muscle spasms to a similar or lesser degree than does morphine.

Tone is increased in the biliary tract, and spasms (particularly of the sphincter of Oddi) and an increase in biliary tract pressure may result. Morphine produces a greater increase in biliary pressure than does meperidine; meperidine produces a greater effect than does codeine. These biliary effects do not always occur with therapeutic doses; some patients may have no change in bile duct diameter or pressure. Biliary spasms may result in plasma amylase and lipase concentrations as much as 2-15 times the normal values.

Genitourinary Effects !!navigator!!

Opiate agonists increase smooth muscle tone in the urinary tract and induce spasms. Although the response of the ureters is quite variable, the drugs may increase tone and amplitude of contractions, especially of the lower third of the ureter. In the urinary bladder, tone of the detrusor muscle is increased, possibly resulting in urinary urgency. Opiate agonists also increase tone of the vesical sphincter which may make urination difficult. These effects, in conjunction with the central effect of the drugs on release of vasopressin, may produce oliguria; however, results of one study suggest that decreased urine output may occur without any apparent release of vasopressin and may be attributed to decreased rate of glomerular filtration and solute excretion. Some clinicians have attributed decreased urine output to decreased renal plasma flow or increased reabsorption. Large doses of opiate agonists may cause bronchoconstriction, but this effect is rarely seen with therapeutic doses.

Morphine and its congeners in therapeutic doses may prolong labor. There are conflicting reports on the effect of meperidine on the progress of labor. Generally, the effect of opiate agonists on the pregnant uterus appears to depend on the time of administration; administration of the drugs during the latent phase of the first stage of labor or before cervical dilation of 4-5 cm has occurred will probably hamper the progress of labor. In the uterus made hyperactive by oxytocics, morphine tends to restore uterine tone and contractions to a normal level. Although meperidine may have little effect on the normal contracting uterus late in pregnancy, if oxytocics have been administered, meperidine tends to increase uterine tone and contractions.

Cardiovascular Effects !!navigator!!

Most opiate agonists have little cardiovascular effect when given in therapeutic doses to supine patients. When the supine patient who has received an opiate agonist assumes a head-up position, however, orthostatic hypotension and fainting may occur as a result of peripheral vasodilation, particularly in volume-depleted patients. Dilation of peripheral blood vessels may be caused by opiate agonist-induced release of histamine or by depression of the vasomotor center in the medulla. Large doses of opiate agonists may produce hypotension, even in the supine patient. In addition, large doses and/or rapid administration of opiate agonists may produce bradycardia as a result of stimulation of medullary vagal nuclei. Meperidine may produce either bradycardia or tachycardia.

Effects on Histamine !!navigator!!

Although meperidine and its congeners may have some antihistaminic activity, these drugs also cause histamine release although it may be less than that produced by morphine. Sufentanil and fentanyl are less potent stimulators of histamine release than are meperidine or morphine. Manifestations of histamine release and/or peripheral dilation also include flushing, pruritus, red eyes, and sweating.

Endocrine Effects !!navigator!!

Opiate agonists exert endocrinologic effects, some of which may be related to CNS effects. The drugs generally stimulate release of vasopressin. Although opiate agonists have been reported to stimulate the release of corticotropin in animals, the drugs generally inhibit the stress-induced (e.g., associated with surgery) release of corticotropin and the release of gonadotropins (i.e., luteinizing hormone, follicle-stimulating hormone) from the pituitary resulting in decreased plasma and urinary 17-hydroxycorticosteroid and 17-ketosteroid concentrations; however, the functions of the adrenal gland and sex organs are not necessarily suppressed and usually exhibit a normal response to administration of exogenous corticotropin and chorionic gonadotropin. The drugs inhibit the release of thyrotropin from the adenohypophysis leading to a decrease in release of thyroid hormone. Opiate agonists may produce hyperglycemia by an action on paraventricular receptor sites near the foramen of Monro or by stimulating release of epinephrine. Basal metabolic rate may be decreased by 10-20% in patients receiving opiate agonists.

Other Effects !!navigator!!

Opiate agonists may also decrease olfactory and auditory acuity.

Pharmacokinetics

Absorption and Distribution !!navigator!!

Some opiate agonists are well absorbed following oral or rectal administration, but others must be administered parenterally. Individual opiate agonists differ in onset and duration of action. Following subcutaneous administration, rates of absorption and onset of action differ because of differences in solubility and/or rate of dissolution. Opiate agonists are rapidly removed from the blood stream and distributed in decreasing order of concentration into skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen, and brain. The drugs readily penetrate the placental barrier.

Elimination !!navigator!!

Opiate agonists are metabolized mainly in the liver, the microsomes in the endoplasmic reticulum being the major site of metabolism. The drugs are also metabolized in the CNS, kidneys, lungs, and placenta. Opiate agonists undergo conjugation with glucuronic acid, hydrolysis, oxidation, and/or N - or O -dealkylation. The drugs are excreted principally in urine in the unchanged form and as metabolites; small amounts are excreted in the feces.

Some opiate agonists (e.g., codeine, fentanyl, hydrocodone, methadone, oxycodone, tramadol) undergo metabolism via the cytochrome P-450 (CYP) microsomal enzyme system.184,187,188,189,216,263,264,266,267,268,269,270 Methadone is metabolized mainly by CYP isoenzymes 2B6, 2C19, and 3A4, and, to a lesser extent, by CYP isoenzymes 2C9 and 2D6.263 Fentanyl, hydrocodone, and oxycodone are metabolized mainly by CYP3A4, although CYP2D6 also is involved in the metabolism of hydrocodone and oxycodone.264,266,267,268 Codeine and tramadol are metabolized by CYP2D6 and CYP3A4.269,270 Oliceridine also is metabolized mainly by CYP2D6 and CYP3A4, with minor contributions from CYP2C9 and CYP2C19.284 Other opiate agonists (e.g., hydromorphone, morphine, tapentadol) are eliminated mainly via hepatic metabolism to glucuronide conjugates that are excreted in urine.260,271,276,277

Pharmacogenomics

Genetic polymorphism of CYP2D6 may cause variations in individual drug response and should be considered as a factor when differences in efficacy or toxicity of drugs metabolized by this pathway are observed.210,211,213,215,284 Serious adverse reactions have been reported in individuals who are ultrarapid metabolizers of codeine because they convert codeine to morphine (its active metabolite) at a higher rate.208,211,213 (See Codeine 48:08 and also see Codeine 28:08.08.)

Chemistry

Opiate agonists encompass a group of naturally occurring, semisynthetic, and synthetic drugs that stimulate opiate receptors and effectively relieve pain without producing loss of consciousness.

The term “opiate” has been used in the medical literature to describe drugs that are opium derivatives, and “opioid” has been used to describe opium derivatives as well as drugs that are not opium derivatives but are, at least to some extent, opium- or morphine-like in their effects and to describe endogenous peptides (e.g., enkephalins) that have morphine-like activity.117,118,119 Using these definitions, drugs with pharmacologic effects that result in part from agonist activity at opiate receptors100,101,102,103,104,107,108,109,110,111,112,113,114,135,226,228,229 but that are not opium derivatives nor semisynthetic derivatives of morphine or thebaine (e.g., tapentadol, tramadol)100,115,116,224,225,226,227,230 would not be considered an “opiate” but would be considered an “opioid.” However, the terms “opiate” and “opioid” also have been used interchangeably to describe the receptors and associated agonist and antagonist activity of drugs (e.g., morphine) and other mediators at these receptors.117,118,119,120,121,122,123 In the AHFS Pharmacologic-Therapeutic Classification©, the term “opiate agonist” is applied to any drug, regardless of chemical origin, whose pharmacologic and/or toxicologic effects result to an important degree from agonist activity at opiate receptors. The emphasis in the AHFS Classification is on the actual effects of the drugs rather than on chemical derivation. While the term “opioid agonist” also has been applied to drugs that stimulate opiate receptors,117,118,119 the AHFS Pharmacologic-Therapeutic Classification© employs “opiate” rather than “opioid” as the modifier for agonist (and antagonist) activity since true opiate receptors, not opiate- like (i.e., opi- oid ) receptors, are affected.120,121,122,123 Therefore, although drugs like tapentadol and tramadol do not fit the classic definition of an opiate (i.e., if they are not opium derivatives nor semisynthetic derivatives),100,115,116,117,118,119,224,225,226,227,230 these drugs are classified as opiate agonists in AHFS Drug Information because they possess agonist activity at opiate receptors.100,101,102,103,104,107,108,109,110,111,112,113,114,135,226,228,229

Chemically, opiate agonists generally may be classified as phenanthrene derivatives, phenylpiperidine derivatives, or diphenylheptane derivatives. Oliceridine is structurally unrelated to morphine or other µ-opiate receptor agonists.285

Phenanthrene Derivatives !!navigator!!

codeine

levorphanol tartrate

concentrated opium alkaloids hydrochlorides

morphine sulfate

hydrocodone bitartrate

oxycodone

hydromorphone hydrochloride

oxymorphone hydrochloride

Morphine is the prototype of the phenanthrene-derivative opiate agonists. Etherification of the 3-hydroxyl group (e.g., codeine) decreases analgesic activity. Oxidation of the 6-hydroxyl group (e.g., hydromorphone, oxymorphone) increases analgesic activity. Although levorphanol is a morphinan derivative, it is structurally similar to the phenanthrene-derivative opiate agonists. Most phenanthrene derivatives are analgesics; however, naloxone hydrochloride and naltrexone hydrochloride are essentially pure opiate antagonists (see 28:10), which have little or no analgesic activity. Hydrocodone bitartrate is also used as an antitussive (see 48:08).

Phenylpiperidine Derivatives !!navigator!!

anileridine hydrochloride

meperidine hydrochloride

fentanyl citrate

sufentanil citrate

Meperidine is the prototype of the phenylpiperidine-derivative opiate agonists. Replacement of the N -methyl group of meperidine with a large rigid aralkyl group (e.g., anileridine) increases analgesic activity. Replacement of the N -methyl group of meperidine with a diphenylcyanopropyl group produces diphenoxylate, a compound which is devoid of analgesic activity but has good antidiarrheal activity (see 56:08).

Diphenylheptane Derivatives !!navigator!!

methadone hydrochloride

levomethadyl acetate hydrochloride

Methadone hydrochloride is the prototype of the diphenylheptane-derivative opiate agonists. Levomethadyl acetate hydrochloride (no longer commercially available in the US because of potentially severe adverse cardiac effects) is a synthetic congener of methadone with a delayed onset of action and prolonged duration of effect. Propoxyphene (no longer commercially available in the US), which is closely related structurally to methadone, has mild analgesic activity.

Most opiate agonists are basic in reaction and readily react with acids to form water-soluble salts. Such salts have a wide range of water solubility.

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.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

Only references cited for selected revisions after 1984 are available electronically.

100. Ortho-McNeil Pharmaceutical. Ultram® (tramadol hydrochloride) tablets prescribing information. Raritan, NJ. 1995 Mar 3.

101. Lehmann KA. Tramadol for the management of acute pain. Drugs . 1994; 47(Suppl 1):19-32. [PubMed 7517822]

102. Dayer P, Collart L, Desmeules J. The pharmacology of tramadol. Drugs . 1994; 47(Suppl 1):3-7. [PubMed 7517823]

103. Lee CR, McTavish D, Sorkin EM. Tramadol: a preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs . 1993; 46:313-40. [PubMed 7691519]

104. Reynolds JEF, ed. Martindale: the extra pharmacopoeia. 30th ed. London: The Pharmaceutical Press; 1993:1097-8.

105. Besson JM, Vickers MD. Tramadol analgesia: synergy in research and therapy. Drugs . 1994; 47(Suppl 1):1-2. [PubMed 7517820]

106. Budd K. Chronic pain—challenge and response. Drugs . 1994; 47(Suppl 1):33-8. [PubMed 7517824]

107. Anon. New oral analgesic, tramadol, gains marketing approval. Am J Health-Syst Pharm . 1995; 52:1153-4. [PubMed 7656104]

108. Anon. Tramadol-a new analgesic. Drug Ther Bull . 1994; 32:85-7. [PubMed 7635011]

109. Vickers MD. Monographs in the Drug and Therapeutics Bulletin seem to be biased. BMJ . 1995; 310:663. [PubMedCentral][PubMed 7703769]

110. Collier J. Monographs in the Drug and Therapeutics Bulletin : bulletin editor's reply. BMJ . 1995; 310:663. [PubMedCentral]

111. Osipova NA, Novikov GA, Beresnev VA et al. Analgesic effect of tramadol in cancer patients with chronic pain: a comparison with prolonged-action morphine sulfate. Curr Ther Res Clin Exp . 1991; 50:812-21.

112. Hummel T, Hummel G, Friedel I et al. A comparison of the antinociceptive effects of imipramine, tramadol and anpirtoline. Br J Clin Pharmacol . 1994; 37:325-33. [PubMedCentral][PubMed 8018453]

113. Eggers K, Power I. Tramadol hydrochloride-not just another opioid agonist. Br J Clin Pharmacol . 1995; 39:338. [PubMedCentral][PubMed 7619680]

114. Hummel T, Kobal G. Reply: Tramadol hydrochloride—not just another opioid agonist. Br J Clin Pharmacol . 1995; 39:339. [PubMedCentral]

115. Ortho-McNeil Pharmaceuticals, Raritan, NJ: Personal communication.

116. Grond S, Zech D, Lynch J et al. Tramadol—a weak opioid for relief of cancer pain. Pain Clinic . 1992; 5:241-7.

117. Martin WR. Pharmacology of opioids. Pharmacol Rev . 1984; 35:283-323.

118. Jaffe JH, Martin WR. Opioid analgesics and antagonists. In: Gilman AG, Rall TW, Nies AS et al, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press; 1990:485-51.

119. Brown RM, Clouet DH, Friedman DP et al. Opiate receptor subtypes and brain function. NIDA Res Monogr Ser . 1986; 71:1-188.

120. Snyder SH. The opiate receptor. Ann Intern Med . 1974; 81:534-40. [PubMed 4213465]

121. Pert CB, Snyder SH. Opiate receptor: demonstration in nervous tissue. Science . 1973; 179:1011-4. [PubMed 4687585]

122. Pert CB, Snyder SH. Properties of opiate receptor binding in rat brain. Proc Natl Acad Sci USA . 1973; 70:2243-7. [PubMedCentral][PubMed 4525427]

123. Pert CB, Pasternak G, Snyder SH. Opiate agonists and antagonists discriminated by receptor binding in brain. Science . 1973; 182:1359-61. [PubMed 4128222]

124. Agency for Health Care Policy and Research. Management of cancer pain: adults. Am J Hosp Pharm . 1994; 51:1643-56. [PubMed 7942889]

125. Agency for Health Care Policy and Research. Acute pain management: operative or medical procedures and trauma, part 1. Clin Pharm . 1992; 11:309-31. [PubMed 1563227]

126. Agency for Health Care Policy and Research. Acute pain management: operative or medical procedures and trauma, part 2. Clin Pharm . 1992; 11:391-414. [PubMed 1582131]

127. McCormack JP, Warriner CB, Levine M et al. A comparison of regularly dosed oral morphine and on-demand intramuscular morphine in the treatment of postsurgical pain. Can J Anaesth . 1993; 40:819-24. [PubMed 8403175]

128. Anon. Principles of analgesic use in the treatment of acute pain and cancer pain. 3rd ed. Skokie, IL: American Pain Society; 1992.

129. Marks RM, Sachar EJ. Undertreatment of medical inpatients with narcotic analgesics. Ann Intern Med . 1973; 78:173-81. [PubMed 4683747]

130. Sriwatanakul K, Weis OF, Alloza JL et al. Analysis of narcotic analgesic usage in the treatment of postoperative pain. JAMA . 1983; 250:926-9. [PubMed 6134850]

131. Oden RV. Acute postoperative pain: incidence, severity, and the etiology of inadequate treatment. Anesthesiol Clin North Am . 1989; 7:1-15.

132. Shannon M, Berde CB. Pharmacologic management of pain in children and adolescents. Pediatr Clin North Am . 1989; 36:855-71. [PubMed 2569181]

133. Boulanger A, Choiniöre M, Roy D et al. Comparison between patient-controlled analgesia and intramuscular meperidine after thoracotomy. Can J Anaesth . 1993; 40:409-15. [PubMed 8513519]

134. Hammack JE, Loprinzi CL. Use of orally administered opioids for cancer-related pain. Mayo Clin Proc . 1994; 69:384-90. [PubMed 7513374]

135. Sunshine A, Olson NZ, Zighelboim I et al. Analgesic oral efficacy of tramadol hydrochloride in postoperative pain. Clin Pharmacol Ther . 1992; 51:740-6. [PubMed 1351804]

136. Knoll Laboratories. Vicoprofen® (hydrocodone bitartrate and ibuprofen) tablets prescribing information (dated 1997 Sep). In: Physicians' desk reference. 52nd ed. Montvale, NJ: Medical Economics Company Inc; 1998(suppl B):B55-7.

137. Knoll Laboratories. Vicodin HP® (hydrocodone bitartrate and acetaminophen) tablets prescribing information (dated 1996 May). In: Physicians' desk reference. 52nd ed. Montvale, NJ: Medical Economics Company Inc; 1998:1365-6.

138. UCB Pharma. Lortab® (hydrocodone bitartrate and acetaminophen) tablets and elixir prescribing information (dated 1997 Jun). In: Physicians' desk reference. 52nd ed. Montvale, NJ: Medical Economics Company Inc; 1998:2926-8.

139. Watson Laboratories. Norco® (hydrocodone bitartrate and acetaminophen) tablets prescribing information (1996 Sep 11). In: Physicians' desk reference. 52nd ed. Montvale, NJ: Medical Economics Company Inc; 1998:2986-7.

140. Ryan TJ, Antman EM, Brooks NH et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction: 1999 update: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Circulation . 1999; 100(9):1016-30. [PubMed 10468535]

141. Trzepacz P, Breitbart W, Levenson J et al for the American Psychiatric Association Working Group on Delirium. Practice guideline for the treatment of patients with delirium. Am J Psychiatry . 1999; 156(Supp 5):1-20.

142. Astra Pharmaceuticals. Morphine Sulfate injection prescribing information. In: Physicians' desk reference. 53rd ed. Montvale, NJ: Medical Economics Company Inc; 1999:573-4.

143. Haehl M. Dear healthcare professional letter regarding adverse cardiac events associated with use of levomethadyl acetate hydrochloride. Columbus, OH: Roxane Laboratories; 2001 Apr 11. From the FDA website. [Web]

144. Roxane Laboratories. Orlaam® (levomethadyl acetate hydrochloride) oral solution prescribing information. Columbus, Ohio; 2000 Jun.

145. Maurer PM, Bartkowski RR. Drug interactions of clinical significance with opioid analgesics. Drug Saf . 1993; 8:30-48. [PubMed 8471186]

146. Sternbach H. The serotonin syndrome. Am J Psychiatry . 1991; 148:705-13. [PubMed 2035713]

147. Nierenberg DW, Semprebon M. The central nervous system serotonin syndrome. Clin Pharmacol Ther . 1993; 53:84-8. [PubMed 8257462]

148. Mills KC. Serotonin syndrome. Am Fam Physician . 1995; 52:11475-82.

149. Reynolds RD. Serotonin syndrome: what family physicians need to know. Am Fam Physician . 1995; 52:1263-71. [PubMed 7572545]

150. Sporer KA. The serotonin syndrome. Implicated drugs, pathophysiology and management. Drug Saf . 1995; 13:94-104. [PubMed 7576268]

151. Kline SS, Mauro LS, Scala-Barnett DM et al. Serotonin syndrome versus neuroleptic malignant syndrome as a cause of death. Clin Pharm . 1989; 8:510-4. [PubMed 2568897]

152. Purdue Pharma. Statement regarding suspension of 160 mg OxyContin® tablets. Stamford, CT; 2001 May 11. Press release.

153. Purdue Pharma. Personal communication.

154. Endo Pharmaceuticals. Percocet® (oxycodone hydrochloride and acetaminophen) tablets prescribing information. Wilmington, DE. 2000 Jan.

155. Endo Pharmaceuticals. Percodan® (oxycodone hydrochloride and aspirin) tablets prescribing information. Wilmington, DE 1999 Nov.

156. Xanodyne Pharmaceuticals Inc. RoxicodoneTM (oxycodone hydrochloride) tablets prescribing information. Newport, KY; 2006 Mar.

157. FDA strengthens warning for oxycontin. FDA Talk Paper. Rockville, MD; Food and Drug Administration; 2001 Jul 25.

158. Young D. Federal reports say oxycodone abuse is on the rise. Am J Health-Syst Pharm . 2001; 58:1175-79. [PubMed 11449872]

159. Oxycontin diversion and abuse. Information Bulletin. U.S. Department of Justice. Johnstown, PA; National Drug Intelligence Center.; 2001 Jan.

160. Anon. Oxycodone and oxycontin. Med Letter Drugs Ther . 2001; 43:80-1.

161. Raffa RB. Pharmacology of oral combination analgesics: rational therapy for pain. J Clin Pharm Ther . 2001; 26:257-64. [PubMed 11493367]

162. Bauman TJ. Pain management. In: DiPiro JT, Talbert RL, Yee GC et al., eds. Pharmacotherapy: a pathophysiologic approach. 5th ed. Stamford: Appleton and Lan 2002:1014-26.

163. Taylor EC, Koo PJS. Pain. In: Young LY, Koda-Kimble MA, eds. Applied therapeutics: the clinical use of drugs. 7th ed. Vancouver, WA: Applied Therapeutics, Inc; 2001:7-1-7-40.

164. Portenoy RK, Lesage P. Management of cancer pain. Lancet . 1999; 353:1695-700. [PubMed 10335806]

165. O'Connor PG, Kosten TR. Rapid and ultrarapid opioid detoxification techniques. JAMA . 1998; 279:229-34. [PubMed 9438745]

166. Purdue Pharma L.P. Oxycontin® (oxycodone HCl controlled release) tablets prescribing information. Stamford, CT; 2001 Jul.

167. Matchar DB, Young WB, Rosenberg JH et al. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management of acute attacks. St. Paul, MN; 2001. From the American Academy of Neurology web site. [Web]

168. American Pain Society. Principles of analgesic use in the treatment of acute pain and cancer pain. 4th edition. Glenview, IL; 1999.

169. Xanodyne Pharmaceuticals. Oramorph® SR (morphine sulfate) sustained release tablets prescribing information. Newport, KY. 2006 Feb.

170. Purdue Pharma. MS Contin® (morphine sulfate) controlled-release tablets prescribing information. Stamford CT. 2005 Nov 3.

171. Ligand Pharmaceuticals. Avinza® (morphine sulfate) extended-release capsules prescribing information. San Diego, CA. 2005 Dec..

172. Actavis Kadian. Kadian® (morphine sulfate extended-release capsules) prescribing information. Morristown, NJ. 2009 Feb.

173. Baxter. Morphine sulfate injection prescribing information. Deerfield, IL. 1999 Apr

174. Society of Critical Care Medicine and American Society of Health-System Pharmacists: Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Am J Health-Syst Pharm . 2002; 59:150-78.

175. Purdue Pharma L.P. OxyContin® (oxycodone HCl controlled release) tablets patient information. Stamford, CT 2002 Jan.

176. USP DI: drug information for the health care professional. 23rd ed. Greenwood Village, CO: Thompson Micromedex; 2003;1:2063-8.

177. American Geriatric Society Panel on Persistent Pain in Older Persons. The management of persistent pain in older persons. J Am Geriatr Soci . 2002; 50(suppl):S205-24.

178. Freedman GM. Clinical management of common causes of geriatric pain. Geriatrics . 2002; 57:36-41. [PubMed 12040592]

179. Sanofi-Synthelabo. Demerol® (meperidine hydrochloride) tablets and syrup prescribing information. New York, NY; 2002 May.

180. Anon. Principles of analgesic use in the treatment of acute pain and cancer pain. 4th ed. Glenview, IL: American Pain Society; 1994.

181. Jacox A, Carr DB, Payne R et al. Management of cancer pain: clinical practice guideline. No. 9. Rockville, MD: US Department of Health and Human Services, Public Health Service, Agency for Health Care Policy and Research. AHCPR publication No. 94-0592.

182. Food and Drug Administration. 2003 safety alert: Roxanol (morphine sulfate) concentrated oral solution. Rockville, MD; June 2003. From FDA website. [Web]

183. Schobelock MJ. Dear healthcare professional letter: Product discontinuation notice—Orlaam® (levomethadyl hydrochloride acetate) oral solution, 10 mg/mL, CII. Columbus, OH: Roxane Laboratories; 2003 Apr 23.

184. aaiPharma, Inc. Methadone hydrochloride injection prescribing information. Wilmington, NC. 2004 Feb.

185. Anderson R, Saiers JH, Abram S et al. Accuracy in equianalgesic dosing: conversion dilemmas. J Pain Symptom Manage . 2001; 21:397-406. [PubMed 11369161]

186. Roxane Laboratories, Inc. Methadone hydrochloride tablets prescribing information. Columbus, OH. 2000 Dec.

187. Layson-Wolf C, Goode JV, Small RE. Clinical use of methadone. J Pain Palliat Care Pharmacother . 2002; 16:29-59. [PubMed 14650449]

188. Davis MP, Walsh D. Methadone for relief of cancer pain: a review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration. Support Care Cancer . 2001; 9:73-83. [PubMed 11305074]

189. Kharasch ED, Hoffer C, Whittington D et al. Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone. Clin Pharmacol Ther . 2004; 76:250-69. [PubMed 15371986]

190. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med . 2003; 349:1943-53. [PubMed 14614170]

191. Principles of analgesic use in the treatment of acute pain and cancer pain. 5th ed. Glenview, IL: American Pain Society; 2004:14,17.

192. Endo Pharmaceuticals. DepoDur® (morphine sulfate extended-release liposome injection) prescribing information. Chadds Ford, PA. From Skye Pharma web site. Accessed 19 Oct 2005. [Web]

193. Baxter. Duramorph (morphine sulfate injection) preservative free prescribing information. Deerfield, IL. 2004 Dec.

194. Medtronic. Tools for safe patient management. 2006 Jan.

195. Alpharma. Kadian®: important safety information health care professionals. From Kadian website. Accessed 2006 Nov 29 [Web]

196. Faulding Pharmaceutical Co. Morphine sulfate injection prescribing information. Paramus, NJ. 2003 Mar.

197. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson textbook of pediatrics. 17th ed. Philadelphia: Saunders; 2004:2469.

198. Viscusi ER, Schechter LN. Patient-controlled analgesia: finding a balance between cost and comfort. Am J Health-Syst Pharm . 2006; 63(suppl 1):S3-13. [PubMed 16598071]

199. Strassels SA, McNicol E, Suleman R. Postoperative pain management: a practical review, part 1. Am J Health-Syst Pharm . 2005; 62:1904-16. [PubMed 16141110]

200. Bailey PL. Clinical Pharmacology and Applications of Opioid Agonists. In: Bowdle TA, Horita A, Kharasch ED. The pharmacologic basis of anesthesiology. New York: Churchill Livingstone; 1994:83-119.

201. Berde CB, Lehn BM, Yee JD et al. Patient-controlled analgesia in children and adolescents: a randomized, prospective comparison with intramuscular administration of morphine for postoperative analgesia. J Pediatr . 1991; 118:460-6. [PubMed 1999793]

202. aai Pharma. Roxanol® and Roxanol®-T (morphine sulfate) oral solution prescribing information. Wilmington, NC. 2004 Jul.

203. Hudcova J, McNicol E, Quah C et al. Patient controlled opioid analgesia versus conventional opioid analgesia for postoperative pain. Cochrane Database Syst Rev. 2006; 4:CD003348. DOI: 10.1002/14651858.CD003348.pub2.

204. Ginsberg B, Latta KS. Acute pain management. In: Lipman AG, ed. Pain management for primary care clinicians. Bethesda, MD; American Society of Health-System Pharmacists; 2004:123-38.

205. US Food and Drug Administration. FDA public health advisory: use of codeine by some breastfeeding mothers may lead to life-threatening side effects in nursing babies. Rockville, MD; 2007 Aug. From FDA website. [Web]

206. Food and Drug Administration. FDA Alert: Use of codeine produicts in nursing mothers. 2007 Aug. From FDA website. [Web]

207. Food and Drug Administration. Codeine products used by nursing mothers [August 17, 2007]. Medwatch alert. Rockville, MD; 2007 Aug. From FDA website. [Web]

208. Koren G, Cairns J, Chitayat D et al. Pharmacogenetics of morphine poisoning in a breastfed neonate of a codeine-prescribed mother. Lancet . 2006; 368:704. [PubMed 16920476]

209. Kirchheiner J, Schmidt H, Tzvetkov M et al. Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication. Pharmacogenomics J . 2007; 7:257-65. [PubMed 16819548]

210. Meyer UA. Pharmacogenetics and adverse drug reactions. Lancet . 2000; 356:1667-71. [PubMed 11089838]

211. Gasche Y, Daali Y, Fathi M et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med . 2004; 351:2827-31. [PubMed 15625333]

212. Roche Molecular Systems, Inc. AmpliChip CYP450 Test for in vitro diagnostic use. Branchburg, NJ; 2007 July.

213. Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral codeine: a genetic variant-an ultra-rapid metabolizer. Paediatr Anaesth . 2007; 17:684-87. [PubMed 17564651]

214. US Food and Drug Administration. FDA warning on codeine use by nursing mothers. FDA News August 17, 2007. From FDA website. [Web]

215. Weinshilboum R. Inheritance and drug response. N Engl J Med . 2003; 348:529-37. [PubMed 12571261]

216. Cephalon, Inc. Fentora® (fentanyl citrate) buccal tablet prescribing information. Salt Lake City, UT; 2007 Apr.

217. US Food and Drug Administration. FDA approves name change for heartburn drug Kapidex. Rockville, MD; 2010 Mar 4. News release from FDA website. [Web]

222. Takeda Pharmaceuticals America. Dexilant® (dexlansoprazole) delayed-release capsules prescribing information. Deerfield, IL; 2010 Mar.

223. Institute for Safe Medication Practices. Progress with preventing name confusion errors. ISMP Medication Safety Alert! Acute Care edition. Horsham, PA; 2007 Aug 9. From ISMP website. [Web]

224. Ortho-McNeil-Janssen. Nucynta® (tapentadol) immediate-release tablets prescribing information. Raritan, NJ; 2009 Mar.

225. Hartrick CT. Tapentadol immediate release for the relief of moderate-to-severe acute pain. Expert Opin Pharmacother . 2009; 10:2687-96. [PubMed 19795998]

226. Tzschentke TM, Christoph T, Kögel B et al. (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl): a novel mu-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther . 2007; 323:265-76. [PubMed 17656655]

227. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 22-3304: Summary review for tapentadol. From FDA web site. [Web]

228. Guay DR. Is tapentadol an advance on tramadol?. Consult Pharm . 2009; 24:833-40. [PubMed 20092221]

229. Wade WE, Spruill WJ. Tapentadol hydrochloride: a centrally acting oral analgesic. Clin Ther . 2009; 31:2804-18. [PubMed 20110020]

230. . Tapentadol (Nucynta)--a new analgesic. Med Lett Drugs Ther . 2009; 51:61-2. [PubMed 19661853]

231. Drug Enforcement Administration. Schedules of controlled substances: placement of tapentadol into Schedule II. 21 CFR Part 1308. Final Rule. [Docket No. DEA-319F] Fed Regist. 2009; 74:23790-3.

232. US Food and Drug Administration. Drug safety communication: FDA recommends against the continued use of propoxyphene. Rockville, MD; 2010 Nov 19. From FDA website ([Web]).

233. Balakrishnan SM, Dang Q, Zhang J et al. Interdisciplinary review team for QT studies consultation: multiple ascending dose (MAD) study review. Available at FDA website ([Web]). Accessed 2011 Feb 8.

234. Roxane Laboratories, Inc. Dear healthcare professional letter: important drug safety information regarding morphine sulfate oral solution 100 mg per 5 mL (20 mg/mL). Columbus, OH; 2010 Dec. Available from FDA website. [Web]

235. Food and Drug Administration. Morphine sulfate oral solution 100 mg per 5 mL (20 mg/mL): medication use error - reports of accidental overdose. Medwatch safety alert. Rockville, MD; 2011 Jan 10. From FDA website. Accessed 2011 Jul 8. [Web]

236. Roxane Laboratories, Inc. Morphine sulfate oral solution prescribing information. Columbus, OH; 2011 Apr.

237. Food and Drug Administration. Morphine sulfate oral solution (NDA 22-195/S-002; 10 mg/5 mL, 20 mg/5 mL, 100 mg/5 mL) risk evaluation and mitigation strategy (REMS). Available from FDA website. Accessed 1 Jul 2011. [Web]

238. Purdue Pharma. Dilaudid® (hydromorphone hydrochloride) oral liquid and tablets prescribing information. Stamford, CT; 2009 Oct 21.

239. Purdue Pharma. Dilaudid® and Dilaudid-HP® (hydromorphone hydrochloride) injection prescribing information. Stamford, CT; 2011 Jul .

240. Quigley C. Hydromorphone for acute and chronic pain. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD003447. DOI: 10.1002/14651858.CD003447.

241. Principles of analgesic use in the treatment of acute pain and cancer pain. 5th ed. Glenview, IL: American Pain Society; 2004:13-41.

242. Sessler CN, Varney K. Patient-focused sedation and analgesia in the ICU. Chest . 2008; 133:552-65. [PubMed 18252923]

243. Jacobi J, Fraser GL, Coursin DB et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med . 2002; 30:119-41. [PubMed 11902253]

244. Murray A, Hagen NA. Hydromorphone. J Pain Symptom Manage . 2005; 29(5 Suppl):S57-66. [PubMedCentral]

245. In: Kliegman RM, Behrman RE, Jenson HB et al, eds. Nelson textbook of pediatrics. 18th ed. Philadelphia: Saunders; 2007:2460.

246. Mallinckrodt. Exalgo® (hydromorphone hydrochloride) extended-release tablets prescribing information. Hazelwood, MO; 2010 Nov.

247. Food and Drug Administration. Exalgo® (hydromorphone hydrochloride) extended-release tablets. Risk Evaluation and Mitigation Strategy (REMS) document. Rockville, MD; 2010 Mar 24. From FDA website. [Web]

248. Mallinckrodt. Exalgo® (hydromorphone hydrochloride) extended-release tablets medication guide. Hazelwood, MO; 2010 Nov.

249. Lannett Company, Inc. Codeine sulfate tablets prescribing information. Philadelphia, PA; 2013 Apr. From DailyMed website

250. TAGI Pharma, Inc. Codeine sulfate oral solution prescribing information. South Beloit, IL; 2013 Apr. From DailyMed website.

251. Food and Drug Administration. Safety review update of codeine use in children; new Boxed Warning and Contraindication on use after tonsillectomy and/or adenoidectomy. FDA News. Rockville, MD; 2013 Feb 20. From FDA website [Web]

252. Kelly LE, Rieder M, van den Anker J et al. More codeine fatalities after tonsillectomy in North American children. Pediatrics . 2012; 129:e1343-7. [PubMed 22492761]

253. Ciszkowski C, Madadi P, Phillips MS et al. Codeine, ultrarapid-metabolism genotype, and postoperative death. N Engl J Med . 2009; 361:827-8. [PubMed 19692698]

254. Voronov P, Przybylo HJ, Jagannathan N. Apnea in a child after oral codeine: a genetic variant - an ultra-rapid metabolizer. Paediatr Anaesth . 2007; 17:684-7. [PubMed 17564651]

255. Qualitest Pharmaceuticals. Acetaminophen and codeine phosphate oral solution prescribing information. Huntsville, AL; 2014 Mar. From DailyMed website.

256. Drug Enforcement Administration. Schedules of controlled substances: placement of tramadol into schedule IV. 21 CFR Part 1308. Final rule. [Docket No. DEA-351] Fed Regist . 2014; 79:37623-30.

257. Hydrocodone. In: Briggs GG, Freeman RK. Drugs in pregnancy and lactation. 10th ed. Philadelphia, PA: Wolters Kluwer; 2015: 659-61.

258. 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.

259. Roxane Laboratories. Dolophine® (methadone hydrochloride) tablets prescribing information. Columbus, OH; 2014 Apr.

260. Pfizer. Avinza® (morphine sulfate) extended-release capsules prescribing information. New York, NY; 2014 Apr.

261. Mallinckrodt. Exalgo® (hydromorphone hydrochloride) extended-release tablets prescribing information. Hazelwood, MO; 2014 Apr.

262. Rappaport RA. Letter to NDA holders of extended-release and long-acting opioids. Labeling supplement and PMR required. Rockville, MD: US Food and Drug Administration; undated. From FDA website. Accessed 2015 Nov 20. [Web]

263. Roxane Laboratories. Dolophine® (methadone hydrochloride) tablets prescribing information. Columbus, OH; 2015 Apr.

264. Zogenix. Zohydro® ER (hydrocodone bitartrate) extended-release capsules prescribing information. San Diego, CA; 2015 Feb.

265. Endo Pharmaceuticals. Opana® (oxymorphone hydrochcloride) tablets prescribing information. Malvern, PA; 2013 Mar.

266. Teva Pharmaceuticals USA. Fentora® (fentanyl citrate) buccal tablets prescribing information. North Wales, PA; 2013 Feb.

267. Janssen Pharmaceuticals. Duragesic® (fentanyl) transdermal system prescribing information. Titusville, NJ; 2014 Apr.

268. Purdue Pharma. Oxycontin® (oxycodone hydrochloride) extended-release tablets prescribing information. Stamford, CT; 2015 Aug.

269. Roxane Laboratories. Codeine sulfate tablets prescribing information. Columbus, OH; 2015 Sep.

270. Janssen Pharmaceuticals. Ultram® (tramadol hydrochloride) tablets prescribing information. Titusville, NJ; 2014 Jul.

271. Purdue Pharma. Dilaudid® and Dilaudid-HP® (hydromorphone hydrochloride) injection prescribing information. Stamford, CT; 2011 Oct .

272. Mallinckrodt. Xartemis® XR (oxycodone hydrochcloride and acetaminophen) extended-release tablets prescribing information. Hazelwood, MO; 2015 Mar.

273. Endo Pharmaceuticals. Percocet® (oxycodone hydrochloride and acetaminophen) tablets prescribing information. Malvern, PA; 2014 Aug.

274. Purdue Pharma. Hysingla® ER (hydrocodone bitartrate) extended-release tablets prescribing information. Stamford, CT; 2015 Feb.

275. Endo Pharmaceuticals. Opana® ER (oxymorphone hydrochcloride) extended-release tablets prescribing information. Malvern, PA; 2014 Apr.

276. Inspiron Delivery Technologies. Morphabond® (morphine sulfate) extended-release tablets prescribing information. Valley Cottage, NY; 2015 Oct.

277. Janssen Pharmaceuticals. Nucynta® (tapentadol hydrochloride) tablets prescribing information. Titusville, NJ; 2013 Sep.

278. National Institute on Drug Abuse. The prescription opioid epidemic and heroin. 2015 Oct. From NIDA website. Accessed 2015 Dec 2. [Web]

279. Dart RC, Surratt HL, Cicero TJ et al. Trends in opioid analgesic abuse and mortality in the United States. N Engl J Med . 2015; 372:241-8. [PubMed 25587948]

280. Warner M, Hedegaard H, Chen LH. Trends in drug-poisoning deaths involving opioid analgesics and heroin: United States, 1999-2012. 2014 Dec. From CDC website. [Web]

281. Cicero TJ, Ellis MS, Surratt HL et al. The changing face of heroin use in the United States: a retrospective analysis of the past 50 years. JAMA Psychiatry . 2014; 71:821-6. [PubMed 24871348]

282. Hedegaard H, Chen LH, Warner M. Drug-poisoning deaths involving heroin: United States, 2000-2013. NCHS Data Brief . 2015; :1-8. [PubMed 25932890]

283. National Institute on Drug Abuse. Overdose death rates. 2015 Dec. From NIDA website. Accessed 2015 Dec 11. [Web]

284. Trevena, Inc. Olinvyk® (oliceridine fumarate) injection prescribing information. Chesterbrook, PA; 2021 Mar.

285. Madariaga-Mazón A, Marmolejo-Valencia AF, Li Y et al. Mu-Opioid receptor biased ligands: A safer and painless discovery of analgesics. Drug Discov Today . 2017; 22:1719-1729. [PubMedCentral][PubMed 28743488]

350. Substance Abuse and Mental Health Services Administration (SAMHSA) Clinical guidance for treating pregnant and parenting women with opioid use disorder and their infants (HHS publication no. [SMA] 18-5054). Rockville, MD: SAMHSA. 2018. From SAMHSA website. [Web]

351. Klaman SL, Isaacs K, Leopold A et al. Treating Women Who Are Pregnant and Parenting for Opioid Use Disorder and the Concurrent Care of Their Infants and Children: Literature Review to Support National Guidance. J Addict Med . 2017 May/Jun; 11:178-190. [PubMed 28406856]

352. McQueen K, Murphy-Oikonen J. Neonatal Abstinence Syndrome. N Engl J Med . 2016; 375:2468-2479. [PubMed 28002715]

353. Hudak ML, Tan RC, COMMITTEE ON DRUGS et al. Neonatal drug withdrawal. Pediatrics . 2012; 129:e540-60. [PubMed 22291123]

354. Wachman EM, Schiff DM, Silverstein M. Neonatal Abstinence Syndrome: Advances in Diagnosis and Treatment. JAMA . 2018; 319:1362-1374. [PubMed 29614184]

355. Raffaeli G, Cavallaro G, Allegaert K et al. Neonatal Abstinence Syndrome: Update on Diagnostic and Therapeutic Strategies. Pharmacotherapy . 2017; 37:814-823. [PubMed 28519244]

357. Kocherlakota P. Neonatal abstinence syndrome. Pediatrics . 2014; 134:e547-61. [PubMed 25070299]

358. World Health Organization. Guidelines for the identification and management of substance use and substance use disorders in pregnancy. Geneva, Switzerland: WHO Press, 2014. From WHO website. [Web]

359. Kraft WK, Stover MW, Davis JM. Neonatal abstinence syndrome: Pharmacologic strategies for the mother and infant. Semin Perinatol . 2016; 40:203-12. [PubMed 26791055]

360. Disher T, Gullickson C, Singh B et al. Pharmacological Treatments for Neonatal Abstinence Syndrome: A Systematic Review and Network Meta-analysis. JAMA Pediatr . 2019; [PubMed 30667476]

361. Davis JM, Shenberger J, Terrin N et al. Comparison of Safety and Efficacy of Methadone vs Morphine for Treatment of Neonatal Abstinence Syndrome: A Randomized Clinical Trial. JAMA Pediatr . 2018; 172:741-748. [PubMed 29913015]

362. Kraft WK, Adeniyi-Jones SC, Chervoneva I et al. Buprenorphine for the Treatment of the Neonatal Abstinence Syndrome. N Engl J Med . 2017; 376:2341-2348. [PubMed 28468518]

363. Tolia VN, Murthy K, Bennett MM et al. Morphine vs Methadone Treatment for Infants with Neonatal Abstinence Syndrome. J Pediatr . 2018; 203:185-189. [PubMed 30220442]

365. Ohio Perinatal Quality Collaborative. Updates/changes to the recommended OPQC NAS Protocol. From the Ohio Perinatal Quality Collaborative website. Accessed 2019 Jun 25. [Web]

368. University of Iowa Children's Hospital. Identifying neonatal abstinence syndrome (NAS) and treatment guidelines. Revised 2014 Nov. From the University of Iowa Children's Hospital website. Accessed 2019 Jun 24. [Web]

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 (NAMSDL). Overview of state pain management and prescribing policies. From NAMSDL website. 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]

427. Worthington I, Pringsheim T, Gawel MJ et al. Canadian Headache Society Guideline: acute drug therapy for migraine headache. Can J Neurol Sci . 2013; 40(5 Suppl 3):S1-S80. [PubMed 23968886]

428. Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the american headache society evidence assessment of migraine pharmacotherapies. Headache . 2015; 55:3-20. [PubMed 25600718]

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]

527. O'Gara PT, Kushner FG, Ascheim DD et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation . 2013; 127:e362-425. [PubMedCentral]

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. Seymour S. Letter to manufacturers of opioid antitussives: safety labeling change notification. Silver Spring, MD: US Food and Drug Administration. Accessed 2017 Mar 20. [Web]

705. Food and Drug Administration. Drug safety communication: FDA restricts use of prescription codeine pain and cough medicines and tramadol pain medicines in children; recommends against use in breastfeeding women. Silver Spring, MD; 2017 Apr 20. From FDA website. [Web]

706. US Food and Drug Administration. Drug safety communication: FDA urges caution about withholding opioid addiction medications from patients taking benzodiazepines or CNS depressants: careful medication management can reduce risks. Silver Spring, MD; 2017 Sep 20. From FDA website. [Web]

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]

710. US Food and Drug Administration. Drug safety communication: FDA requires labeling changes for prescription opioid cough and cold medicines to limit their use to adults 18 years and older. Silver Spring, MD; 2018 Jan 11. From FDA website. [Web]

1100. Amsterdam EA, Wenger NK, Brindis RG et al. 2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation . 2014; 130:e344-426. [PubMedCentral]