Opiate Agonists General Statement (Monograph)

Drug class: Opioid Agonists
- Narcotic Analgesics
- Opioids
VA class: CN101

Introduction

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 for Opiate Agonists General Statement

Pain

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 overdosage^{411 431 750} 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 healing^{410 411 412 413} ) 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 dosage^{411 413} 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}

Delirium

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

Acute Pulmonary Edema

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

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

Some opiate agonists, notably codeine and its derivative hydrocodone, are used as cough suppressants. Diphenoxylate and opium preparations are used mainly as antidiarrheal agents (see 56:08).

Detoxification and Maintenance of Opiate Dependence

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 and see Cautions: Precautions and Contraindications.

Neonatal Opiate Withdrawal

Opiate agonists, including morphine and methadone, have been used to manage manifestations of opiate abstinence syndrome (i.e., postnatal withdrawal) in neonates^{† [off-label]} 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}

Opiate Agonists General Statement Dosage and Administration

Administration

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

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:

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

These 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}

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 for Opiate Agonists General Statement

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

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

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

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

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

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

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

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

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

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

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

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 age; 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

Serious adverse events, including deaths, also have been reported in pediatric patients receiving opiate agonists for the management of cough and cold.^{705 710}

Geriatric Precautions

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

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} 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

Drug Interactions

Benzodiazepines and Other CNS Depressants

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

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

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. 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

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

Opiate Antagonists and Opiate Partial Agonists

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

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

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

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

Anticholinergic Agents

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

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

Amphetamines

Dextroamphetamine may enhance opiate agonist analgesia.

Diuretics

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

Acute Toxicity

Manifestations

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

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); 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.^{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. 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. 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.

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

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

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

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

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

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

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

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

Opiate agonists may also decrease olfactory and auditory acuity.

Opiate Agonists General Statement Pharmacokinetics

Absorption and Distribution

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

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}

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 receptors^{100 101 102 103 104 107 108 109 110 111 112 113 114 135 226 228 229} 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

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

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

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.

Related Monographs

For specific dosages and additional information on chemistry and stability, pharmacology, pharmacokinetics, uses, cautions, and drug interactions of the opiate agonists, see the individual monographs in 28:08.08.

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