Professional Drug Information > Anileridine Hydrochloride

Opioid (Narcotic Analgesics Systemic)

This monograph includes information on the following:

1) Anileridine  ^*
2) Butorphanol  ^†
3) Codeine
4) Hydrocodone^‡ *
5) Hydromorphone
6) Levorphanol
7) Meperidine
8) Methadone
9) Morphine
10) Nalbuphine
11) Opium
12) Oxycodone
13) Oxymorphone
14) Pentazocine
15) Propoxyphene

Note: See also individual Buprenorphine (Systemic) and Dezocine (Systemic) monographs.
See also Fentanyl Derivatives (Systemic) for information on alfentanil, fentanyl, and sufentanil.



INN:
Meperidine —Pethidine
Propoxyphene—Dextropropoxyphene

VA CLASSIFICATION
Anileridine
Primary: CN101
Secondary: CN206

Butorphanol
Primary: CN101
Secondary: CN206

Codeine
Oral
Primary: CN101
Secondary: RE301; GA400

Parenteral
Primary: CN101
Secondary: GA400


Hydrocodone
Primary: CN101
Secondary: RE301

Hydromorphone
Oral
Primary: CN101
Secondary: RE301

Parenteral
Primary: CN101
Secondary: CN206; RE301

Rectal
Primary: CN101


Levorphanol
Oral
Primary: CN101

Parenteral
Primary: CN101
Secondary: CN206


Meperidine
Oral
Primary: CN101

Parenteral
Primary: CN101
Secondary: CN206


Methadone
Primary: CN101
Secondary: AD900; RE301

Morphine
Oral
Primary: CN101
Secondary: RE301; GA400

Parenteral
Primary: CN101
Secondary: CN206; RE301; GA400

Rectal
Primary: CN101
Secondary: RE301


Nalbuphine
Primary: CN101
Secondary: CN206

Opium
Oral
Primary: GA400
Secondary: CN101

Parenteral
Primary: CN101


Oxycodone
Primary: CN101

Oxymorphone
Parenteral
Primary: CN101
Secondary: CN206

Rectal
Primary: CN101


Pentazocine
Oral
Primary: CN101

Parenteral
Primary: CN101
Secondary: CN206


Propoxyphene
Primary: CN101


Note: Controlled substance classification—

Drug	U.S.	Canada
Anileridine		N
Butorphanol	II	††
Codeine	II	N
Hydrocodone	‡‡	N
Hydromorphone	II	N
Levorphanol	II	N
Meperidine	II	N
Methadone	II	N §§
Morphine	II	N
Nalbuphine	**	C
Opium	II	N
Oxycodone	II	N
Oxymorphone	II	N
Pentazocine	IV	N
Propoxyphene	IV	N

^** Not a controlled substance in the U.S.
^††  Not commercially available in Canada.
^‡‡ Commercially available in the U.S. only in combination with other active ingredients.
^§§  Available in Canada only through practitioners authorized to treat opioid addicts.
Commonly used brand name(s): 642¹⁵; Astramorph PF⁹; Cotanal-65¹⁵; Darvon¹⁵; Darvon-N¹⁵; Demerol⁷; Dilaudid⁵; Dilaudid-5⁵; Dilaudid-HP⁵; Dolophine⁸; Duramorph⁹; Epimorph⁹; Hycodan⁴; Hydrostat IR⁵; Kadian⁹; Leritine¹; Levo-Dromoran⁶; M S Contin⁹; M-Eslon⁹; M.O.S⁹; M.O.S.-S.R⁹; MS IR⁹; MS.IR⁹; MS/L⁹; MS/L Concentrate⁹; MS/S⁹; MSIR⁹; Methadose⁸; Morphine Extra-Forte⁹; Morphine Forte⁹; Morphine H.P⁹; Morphitec⁹; Nubain¹⁰; Numorphan¹³; OMS Concentrate⁹; Oramorph SR⁹; OxyContin¹²; PMS-Hydromorphone⁵; PMS-Hydromorphone Syrup⁵; PP-Cap¹⁵; Pantopon¹¹; Paveral³; RMS Uniserts⁹; Rescudose⁹; Robidone⁴; Roxanol⁹; Roxanol 100⁹; Roxanol UD⁹; Roxicodone¹²; Roxicodone Intensol¹²; Stadol²; Statex⁹; Statex Drops⁹; Supeudol¹²; Talwin¹⁴; Talwin-Nx¹⁴.

Other commonly used names are:
Dextropropoxyphene—Propoxyphene
Dihydromorphinone —Hydromorphone
Laudanum—Opium Tincture
Levorphan—Levorphanol
Pethidine —Meperidine
Papaveretum—Opium (Parenteral)

^‡ Commercially available in the U.S. only in combination with other active ingredients. See Cough / Cold Combinations (Systemic) , Opioid (Narcotic) Analgesics and Acetaminophen (Systemic), and Opioid (Narcotic) Analgesics and Aspirin (Systemic) .
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^*Not commercially available in the U.S.

^†Not commercially available in Canada.

Category:

Note: All of the opioid analgesics have similar pharmacologic actions; however, clinical uses among specific agents may vary because of actual pharmacokinetic differences, differences in potential for causing adverse effects, lack of specific testing, and/or lack of clinical-use data.



Analgesic—Anileridine;  ^*Butorphanol;  ^†Codeine; Hydrocodone; Hydromorphone; Levorphanol; Meperidine; Methadone; Morphine; Nalbuphine; Opium; Oxycodone; Oxymorphone; Pentazocine; Propoxyphene;
Note: Butorphanol, nalbuphine, and pentazocine are opioid agonist/antagonist analgesics; the other agents in this group are opioid agonist analgesics.



Anesthesia adjunct (opioid analgesic)—Parenteral dosage forms only: Butorphanol; Hydromorphone; Levorphanol; Meperidine; Morphine; Nalbuphine; Oxymorphone; Pentazocine;
Note: For other opioids used primarily as anesthesia adjuncts, see Fentanyl Derivatives (Systemic) .



Antidiarrheal—Codeine; Morphine; Opium Tincture;
Note: For other opioids used only as antidiarrheals, see individual monograph listings for Difenoxin and Atropine , Diphenoxylate and Atropine, Loperamide, and Paregoric .



Antitussive—Codeine (oral dosage forms only); Hydrocodone; Hydromorphone; Methadone; Morphine;
Note: For use of hydromorphone as an antitussive, see Cough - Cold Combinations (Systemic)—Hydromorphone and Guaifenesin .



Suppressant (narcotic abstinence syndrome)—Methadone; Opium Tincture;

Pulmonary edema therapy adjunct— —Morphine;

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Pain (treatment)—Morphine, methadone, and parenteral opium are indicated for relief of severe pain; codeine and propoxyphene are indicated for relief of mild to moderate pain; and the other opioid analgesics are indicated for relief of moderate to severe pain. Oxycodone extended-release tablets are indicated for relief of moderate to severe pain when a continuous, around-the-clock analgesic is needed for an extended period of time.^{95}
—Epidural or intrathecal administration of small doses of opioid analgesics may provide prolonged pain relief. Although administration via these routes may decrease the risk of some side/adverse effects, respiratory depression may occur. Solutions containing a preservative must not be used. Only morphine sulfate is currently commercially available in a dosage form that is FDA–approved for administration via these routes.
—For relief of pain due to acute myocardial infarction, morphine is usually considered the drug of choice. Butorphanol and pentazocine are less desirable than other opioid analgesics for this purpose because they have cardiovascular effects that tend to increase cardiac work. Although nalbuphine has not been reported to adversely affect cardiovascular function in patients with acute myocardial infarction (and may be less likely than morphine to cause hypotension), its effects in patients with severely compromised cardiac function caused by acute myocardial infarction have not been fully determined. Therefore, these agents should be used with caution in such patients.
—Parenterally administered opioid analgesics (except for methadone) are indicated to provide obstetrical analgesia.
—Controlled clinical studies have shown that intrathecal, but not epidural, administration of opioid analgesics provides adequate relief of labor pain. Only a preservative-free solution should be used. Morphine sulfate is the only opioid analgesic currently commercially available in a dosage form that is FDA–approved for administration via these routes.

Anesthesia, general or local, adjunct—Parenteral dosage forms of butorphanol, [hydromorphone] , levorphanol, meperidine, morphine, nalbuphine, oxymorphone, and pentazocine are indicated to supplement general, regional, or local anesthesia^{90}. During surgery, they are often used in conjunction with other agents, such as a combination of an ultrashort-acting barbiturate, a neuromuscular blocking agent, and an inhalation anesthetic (usually nitrous oxide), for the maintenance of “balanced” anesthesia.
—Parenteral dosage forms of most opioid analgesics are indicated to provide analgesic, antianxiety, and sedative effects as presurgical medication. However, other medications, such as benzodiazepines, are more commonly used if the patient is not in pain.

Diarrhea (treatment)—[ Codeine]¹, [morphine] , and opium tincture are indicated for treatment of diarrhea. In diarrhea caused by poisoning, these agents should not be used until the toxic material has been eliminated from the gastrointestinal tract.

Cough (treatment)—Although only codeine (oral dosage forms), hydrocodone, and hydromorphone are indicated as antitussives, all opioid analgesics depress the cough reflex. Meperidine, oxymorphone, and propoxyphene have relatively less antitussive activity than other opioid analgesics, especially in low or moderate doses.
—[Methadone and morphine are sometimes used as antitussives when severe pain is present and coughing cannot be relieved by other means. ]

Opioid (narcotic) abstinence syndrome (prophylaxis and treatment); or
Opioid (narcotic) drug use, illicit (treatment)— Methadone is indicated as a suppressant to permit detoxification. Oral methadone is also indicated as maintenance therapy to discourage addicts from returning to illicit use of other opioid drugs.

Edema, pulmonary, acute (treatment adjunct)—Morphine is indicated as adjunctive therapy in the treatment of acute pulmonary edema secondary to left ventricular failure.
—Oxymorphone is also FDA–approved as an adjunct in the treatment of acute pulmonary edema. However, oxymorphone is rarely if ever used for this indication; morphine is the preferred medication.

[Opioid (narcotic) dependence, neonatal (treatment) ]—Opium tincture is used in diluted form in the treatment of neonatal opioid dependence.

[Pain, during mechanical ventilation, neonatal (treatment) ]—Intravenous administration of morphine is indicated for control of pain during mechanical ventilation in neonates.^{91}

[Pain, postoperative, neonatal (treatment)]—Intravenous administration of morphine is indicated for control of postoperative pain in neonates.^{92}

Unaccepted
Methadone is not recommended for obstetrical analgesia because its long duration of action increases the risk of neonatal respiratory depression.

Oxycodone extended-release tablets are not intended for use as a “prn” (as needed) analgesic.^{95} Oxycodone extended-release tablets are not for use in the immediate post-operative period (the first 12–24 hours) unless the patient was receiving the drug prior to surgery. It is not used for mild pain or for pain not expected to last for an extended period of time.^{95}

¹ Not included in Canadian product labeling.

Pharmacology/Pharmacokinetics

Table 1. Pharmacology/Pharmacokinetics

Drug	Protein Binding	Half-life (hr) *	Elimination
			Primary (% excreted unchanged) †	Secondary
Butorphanol	High	2.5–4	72% Renal (<5)	15% Biliary
Codeine ‡	Very low	2.5–4	Renal (5–15); 10% as unchanged or conjugated morphine
Hydrocodone		3.8	Renal
Hydromorphone		2.6–4	Renal
Levorphanol	Moderate		Renal
Meperidine §	High	2.4–4	Renal (5)
Methadone #	High	15–25; increases with re- peated administration	Renal; rate increased in acidic urine	Biliary
Morphine	Low	2–3	85% Renal (9–12)	7–10% Biliary
Nalbuphine		5	Renal
Opium			Renal	Biliary
Oxycodone		2–3	Renal
Oxymorphone			Renal
Pentazocine	Moderate	2–3	Renal (5–23)	Biliary
Propoxyphene **	High	6–12 (propoxyphene) 30–36 (norpropoxyphene)	Renal (<10)	Biliary

^* Half-life may be increased in geriatric patients because of decreased clearance rate. Also, significant increases have been reported in patients with hepatic cirrhosis for meperidine (6 to 7 hr), morphine, and pentazocine.
^† All opioid analgesics are excreted primarily as metabolites.
^‡ About 10% of a dose is demethylated to morphine, which may contribute to the therapeutic actions.
^§ Metabolite normeperidine is active and toxic (having central nervous system (CNS) excitatory [proconvulsant] activity) and accumulates in patients with renal function impairment.
^# Some metabolites are active; drug and/or metabolites may accumulate with repeated administration.
^** Metabolite norpropoxyphene may be toxic; it is not known whether this metabolite has analgesic activity.

Table 2. Pharmacology/Pharmacokinetics

Drug and Route *	Equivalence †	Time to Peak Concentration (hr)	Peak Plasma Concentration	Therapeutic Effects
				Onset of Analgesic Action (min)	Peak Analgesic Effect (min)	Duration of Action Analgesic (hr) ‡/Antitussive (hr)
Anileridine
Oral	75{90}			15{90}		2–3{90}
Butorphanol
IM	2	0.5–1	2.2 nanograms §/mL	10–30	30–60	3–4
IV				2–3	30	2–4
Codeine
Oral	200			30–45	60–120	4/4–6
IM	120			10–30	30–60	4
SC				10–30		4
Hydrocodone
Oral				10–30	30–60	4–6/4–6
Hydromorphone
Oral	7.5			30	90–120	4
IM	1.5			15	30–60	4–5
IV				10–15	15–30	2–3
SC				15	30–90	4
Rectal	3
Levorphanol
Oral	4			10–60	90–120	4–5
IM	2				60	4–5
IV					Within 20	4–5
SC					60–90	4–5
Meperidine
Oral	300			15	60–90	2–4
IM	75			10–15	30–50	2–4
IV				1	5–7	2–4
SC				10–15	30–50	2–4
Methadone
Oral	20			30–60	90–120	4–6 #
IM	10			10–20	60–120	4–5 #
IV					15–30	3–4 #
Morphine
Oral	60 **
Extended-release tablets						8–12
Other oral dosage forms				Slower than IM	60–120	4–5
IM	10			10–30	30–60	4–5
IV					20	4–5
SC				10–30	50–90	4–5
Epidural				15–60		Up to 24
Intrathecal				15–60		Up to 24
Rectal				20–60
Nalbuphine
IM	10	0.5	48 nanograms §/mL	Within 15	60	3–6
IV				2–3	30	3–4
SC				Within 15		3–6
Opium
Parenteral	13.3
Oxycodone
Oral	30				60	3–4
Oxymorphone
IM	1			10–15	30–90	3–6
IV				5–10	15–30	3–4
SC				10–20		3–6
Rectal	10			15–30	120	3–6
Pentazocine
Oral	180			15–30	60–90	3
IM	60			15–20	30–60	2–3
IV				2–3	15–30	2–3
SC				15–20	30–60	2–3
Propoxyphene
Oral	††	2–2.5	0.05–0.1 mcg/mL	15–60	120	4–6

^* IM=Intramuscular; IV=Intravenous; SC=Subcutaneous.
^† Dose in mg therapeutically equivalent to a 10-mg intramuscular dose of morphine.
^‡  In nontolerant patients only. The first sign of tolerance is usually a decrease in the duration of adequate analgesia. Also, may be increased in geriatric patients because of decreased clearance rate.
^§ Nanograms.
^# Increases with repeated dosing because of accumulation of drug and/or active metabolites.
^** For single doses or occasional use only; with chronic dosing on a fixed schedule, may decrease to 20 or 30 mg.
^††  Dose equivalent to 10 mg of morphine would be too toxic to administer. Values reported under time to peak concentration and peak plasma concentration were determined following a 65-mg dose of propoxyphene hydrochloride or a 100-mg dose of propoxyphene napsylate.


Physicochemical characteristics:
Molecular weight—
    Anileridine: 352.46^{90}
    Butorphanol tartrate: 477.55
    Codeine phosphate: 406.37 (hemihydrate); 397.36 (anhydrous)
    Codeine sulfate: 750.86 (trihydrate); 696.81 (anhydrous)
    Hydrocodone bitartrate: 494.50 (hydrate); 449.46 (anhydrous)
    Hydromorphone hydrochloride: 321.80
    Levorphanol tartrate: 443.49 (dihydrate); 407.46 (anhydrous)
    Meperidine hydrochloride: 283.80
    Methadone hydrochloride: 345.91
    Morphine sulfate: 758.83 (pentahydrate); 668.76 (anhydrous)
    Nalbuphine hydrochloride: 393.91
    Oxycodone hydrochloride: 351.83
    Oxymorphone hydrochloride: 337.80
    Pentazocine hydrochloride: 321.89
    Pentazocine lactate: 375.51
    Propoxyphene hydrochloride: 375.94
    Propoxyphene napsylate: 565.72 (monohydrate); 547.71 (anhydrous)

Mechanism of action/Effect:

Opioid analgesics bind with stereospecific receptors at many sites within the central nervous system (CNS) to alter processes affecting both the perception of pain and the emotional response to pain. Although the precise sites and mechanisms of action have not been fully determined, alterations in release of various neurotransmitters from afferent nerves sensitive to painful stimuli may be partially responsible for the analgesic effects. When these medications are used as adjuncts to anesthesia, analgesic actions may provide dose-related protection against hemodynamic responses to surgical stress.

It has been proposed that there are multiple subtypes of opioid receptors, each mediating various therapeutic and/or side effects of opioid drugs. The actions of an opioid analgesic may therefore depend upon its binding affinity for each type of receptor and on whether it acts as a full agonist or a partial agonist or is inactive at each type of receptor.

At least two types of opioid receptors (mu and kappa) mediate analgesia. A third type of receptor (sigma) may not mediate analgesia; actions at this receptor may produce the subjective and psychotomimetic effects characteristic of pentazocine and, to a lesser extent, butorphanol and nalbuphine. Morphine and other opioid agonists exert their agonist activity primarily at the mu receptor, whereas buprenorphine, nalbuphine, and pentazocine exert agonist activity at the kappa and sigma receptors. Mu receptors are widely distributed throughout the CNS, especially in the limbic system (frontal cortex, temporal cortex, amygdala, and hippocampus), thalamus, striatum, hypothalamus, and midbrain as well as laminae I, II, IV, and V of the dorsal horn in the spinal cord. Kappa receptors are localized primarily in the spinal cord and in the cerebral cortex.

Nalbuphine and pentazocine may displace opioids having only agonist activity from their receptor binding sites and competitively inhibit their actions. The medications may therefore precipitate withdrawal symptoms in patients who are physically dependent on such agonists. Butorphanol appears to have no significant antagonist activity at the mu receptor; in some studies, it failed to produce withdrawal symptoms in patients physically dependent on morphine. However, butorphanol does not substitute for mu-receptor agonists sufficiently to prevent or attenuate withdrawal symptoms caused by abrupt discontinuation of these agonists in physically dependent patients. Also, opioid agonist/antagonist drugs share several pharmacologic actions that differ from those of opioids having only agonist activity; i.e., different respiratory depressant, subjective, psychotomimetic, and hemodynamic effects; lower dependence liability; and reduced severity of withdrawal symptoms produced when they are discontinued after prolonged use.


Antidiarrheal:

Act locally and possibly centrally to alter intestinal motility.



Antitussive:

Suppress the cough reflex by a direct central action, probably in the medulla or pons.



Suppressant (narcotic abstinence syndrome):

Substitute for other opioid drugs when administered orally and prevent or attenuate withdrawal symptoms during detoxification. Withdrawal symptoms that may occur when the substituted opioid is discontinued are usually greatly reduced in severity. With continued administration, methadone may produce cross-tolerance to the euphoric effects of other opioid drugs, thereby reducing the patient's desire for such drugs.


Biotransformation:

Hepatic; also in intestinal mucosa.


Precautions to Consider

Pregnancy/Reproduction

Pregnancy—
Risk-benefit must be considered because opioid analgesics cross the placenta. Regular use during pregnancy may cause physical dependence in the fetus, leading to withdrawal symptoms (convulsions, irritability, excessive crying, tremors, hyperactive reflexes, fever, vomiting, diarrhea, sneezing, and yawning) in the neonate. Use of methadone by pregnant women participating in methadone maintenance programs has also been associated with fetal distress in uteroand low birth weight.

For butorphanol, nalbuphine, pentazocine, and propoxyphene: Although studies in humans have not been done, studies in animals have not shown that these agents cause adverse effects on fetal development (Pentazocine and naloxone tablets—FDA Pregnancy Category C).

For codeine, hydrocodone, hydromorphone, morphine, and opium: Although teratogenic effects in humans have not been documented, controlled studies have not been done. Studies in animals have shown codeine (single dose of 100 mg per kg) to cause delayed ossification in mice and (in doses of 120 mg per kg) increased resorptions in rats, and hydrocodone, hydromorphone, and morphine to be teratogenic in very high doses (FDA Pregnancy Category C).

For anileridine, levorphanol, meperidine, methadone, oxycodone, and oxymorphone: Although teratogenic effects in humans have not been documented, controlled studies have not been done^{90}.


Labor and delivery—

Opioid analgesics, including epidurally or intrathecally administered opioids, readily enter the fetal circulation when used during labor and may cause respiratory depression in the neonate, especially the premature neonate. These agents should be used with caution, if at all, during the delivery of a premature infant. Methadone is not recommended for obstetrical analgesia because its long duration of action increases the risk of neonatal respiratory depression. Also, morphine, hydromorphone, codeine, and possibly other opioids may prolong labor. Intrathecal administration of up to 1 mg of morphine sulfate has little effect on the first stage of labor but may prolong the second stage of labor.

Breast-feeding

Problems in humans with most opioid analgesics have not been documented. Butorphanol, codeine, meperidine, methadone, morphine, and propoxyphene are distributed into breast milk. Information concerning the distribution of other opioid analgesics into breast milk is lacking. With usual analgesic doses, concentrations of those drugs known to be distributed into breast milk are generally low. However, risk-benefit must be considered when methadone is administered to a nursing mother in a methadone maintenance program because use of maintenance doses may cause physical dependence in the infant.

Pediatrics

Children up to 2 years of age may be more susceptible to the effects, especially the respiratory depressant effects, of these medications.

Paradoxical excitation is especially likely to occur in pediatric patients receiving opioid analgesics.


Geriatrics


Geriatric patients may be more susceptible to the effects, especially the respiratory depressant effects, of these medications. Also, geriatric patients are more likely to have prostatic hypertrophy or obstruction and age-related renal function impairment, and are therefore more likely to be adversely affected by opioid-induced urinary retention. In addition, geriatric patients may metabolize or eliminate these medications more slowly than younger adults. Lower doses or longer dosing intervals than those usually recommended for adults may be required, and are usually therapeutically effective, for these patients.


Dental

Opioid analgesics may decrease or inhibit salivary flow, thus contributing to the development of caries, periodontal disease, oral candidiasis, and discomfort.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Table 3. Drug Interactions and/or Related Problems

Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.	Agonist											Agonist/Antagonist
	Legend: I=Codeine II=Hydrocodone III=Hydromorphone IV=Levorphanol				V=Meperidine VI=Methadone VII=Morphine			VIII=Opium IX=Oxycodone X=Oxymorphone XI=Propoxyphene				XII=Butorphanol XIII=Nalbuphine XIV=Pentazocine
	I	II	III	IV	V	VI	VII	VIII	IX	X	XI	XII	XIII	XIV
Acidifiers, urinary, such as: Ammonium chloride Ascorbic acid Potassium or sodium phosphate (acidification of the urine by these medications increases methadone excretion, resulting in decreased methadone plasma concentrations; high doses of urinary acidifiers, such as several grams daily of ammonium chloride, may cause withdrawal symptoms in patients who are dependent on methadone)
» Alcohol or » CNS depression–producing medications, other (See Appendix II ) (concurrent use with opioid analgesics may result in increased CNS depressant, respiratory depressant, and hypotensive effects; caution is recommended and dosage of one or both agents should be reduced. In addition, some phenothiazines increase, while others decrease, the effects of opioid analgesics used as adjuncts to anesthesia)
(concurrent use with other CNS depressants having habituation potential may increase the risk of habituation)
Amphetamines {18} (amphetamines may potentiate the analgesic effects of meperidine; however, concurrent use of the 2 medications is not recommended because the monoamine oxidase inhibiting effect of amphetamines may increase the risk of hypotension, severe respiratory depression, coma, convulsions, hyperpyrexia, vascular collapse, and death)
(an overdose of propoxyphene may potentiate the CNS stimulating effects of amphetamines; fatal convulsions can result)
Anticholinergics or other medications with anticholinergic activity (See Appendix II ) (concurrent use with opioid analgesics may result in increased risk of severe constipation, which may lead to paralytic ileus, and/or urinary retention)
Anticoagulants, coumarin- or indandione-derivative (meperidine and propoxyphene have been reported to increase the effects of these anticoagulants; although clinical significance has not been established, the possibility should be considered that adjustment of anticoagulant dosage based on prothrombin time determinations may be necessary during and following concurrent use)
Antidiarrheals, antiperistaltic, such as: Difenoxin and atropine Diphenoxylate and atropine Kaolin, pectin, belladonna alkaloids, and opium Loperamide Opium tincture Paregoric (concurrent use with an opioid analgesic may increase the risk of severe constipation as well as central nervous system [CNS] depression)
Antihypertensives, especially ganglionic blockers such as guanadrel, guanethidine, and mecamylamine, or Diuretics or Hypotension-producing medications, other (See Appendix II) (hypotensive effects of these medications may be potentiated when used concurrently with opioid analgesics, leading to increased risk of orthostatic hypotension; patients should be monitored during concurrent use)
» Buprenorphine (buprenorphine is a partial mu-receptor agonist with high affinity for, and a slow rate of dissociation from, the mu receptor; if administered prior to another opioid agonist, it may reduce the therapeutic effects of the other opioid; in one study in opioid addicts receiving chronic administration of 8 mg of buprenorphine per day, the effects of large doses [up to 120 mg] of morphine were blocked during buprenorphine therapy and for at least 30 hours following the last dose of buprenorphine)
(buprenorphine may also have some antagonist activity at the kappa receptor; the possibility should be considered that it may also reduce the therapeutic effects of subsequently administered butorphanol, nalbuphine, or pentazocine)
(buprenorphine antagonizes the respiratory depressant effects of large doses of previously administered mu-receptor agonists; however, additive respiratory depression may occur if buprenorphine is administered in conjunction with low doses of other mu-receptor agonists or with kappa-receptor agonists)
(buprenorphine may precipitate withdrawal symptoms in physically dependent patients who are chronically receiving potent mu-receptor agonists; however, because of its partial agonist activity, buprenorphine may partially suppress spontaneous withdrawal symptoms caused by abrupt discontinuation of these agonists)
» Carbamazepine (concurrent use with propoxyphene may result in decreased carbamazepine metabolism and lead to increased carbamazepine blood concentration and toxicity; concurrent use is not recommended)
Hydroxyzine (concurrent use with opioid analgesics may result in increased analgesia as well as increased CNS depressant and hypotensive effects)
Metoclopramide (opioid analgesics may antagonize the effects of metoclopramide on gastrointestinal motility)
» Monoamine oxidase (MAO) inhibitors, including furazolidone, pargyline, and procarbazine (concurrent use with meperidine has resulted in unpredictable, severe, and sometimes fatal reactions, including immediate excitation, sweating, rigidity, and severe hypertension, or, in some patients, hypotension, severe respiratory depression, coma, seizures, hyperpyrexia, and cardiovascular collapse; meperidine is contraindicated in patients who have received an MAO inhibitor within 14 to 21 days)
(other opioid analgesics may be used cautiously and in reduced dosage in patients receiving MAO inhibitors; however, it is recommended that a small test dose [1/4 of the usual dose] or several small incremental test doses over a period of several hours first be administered to permit observation of any interaction)
Naloxone (antagonizes the analgesic, CNS, and respiratory depressant effects of opioid analgesics; however, larger doses may be required to reverse the effects of butorphanol, nalbuphine, pentazocine, or propoxyphene than are needed to reverse the effects of other opioids; also, because naloxone may precipitate withdrawal symptoms in physically dependent patients, dosage of naloxone should be carefully titrated when used to treat opioid overdosage in dependent patients)
» Naltrexone (administration of naltrexone to a patient physically dependent on opioid drugs will precipitate withdrawal symptoms; symptoms may appear within 5 minutes of naltrexone administration, persist for up to 48 hours, and be difficult to reverse)
(naltrexone blocks the therapeutic effects of opioids [i.e., analgesic, antidiarrheal, and antitussive]; naltrexone therapy should not be initiated in patients receiving these agents for therapeutic purposes; also, patients receiving naltrexone should be advised to use alternative medications when necessary)
(administration of increased doses of opioids to override naltrexone blockade of opioid receptors may result in increased and prolonged respiratory depression and/or circulatory collapse)
(naltrexone should be discontinued several days prior to elective surgery if administration of an opioid prior to, during, or following surgery is unavoidable)
(the efficacy of naltrexone in antagonizing opioid effects not mediated via opioid receptors [i.e., those that may be caused by histamine release, such as facial swelling, itching, generalized erythema, hives, and, to some extent, hypotension] has not been fully determined; naltrexone may not antagonize these effects completely)
Neuromuscular blocking agents and possibly other medications having some neuromuscular blocking activity (respiratory depressant effects of neuromuscular blockade may be additive to central respiratory depressant effects of opioid analgesics; increased or prolonged respiratory depression [apnea] or paralysis may occur but is of minor clinical significance if the patient is being mechanically ventilated; however, caution and careful monitoring of the patient are recommended during and following concurrent or sequential use, especially if there is a possibility of incomplete reversal of neuromuscular blockade postoperatively)
Nicotine chewing gum or Other smoking deterrents or Smoking, tobacco, or cessation of (tobacco smoking may increase the metabolism of propoxyphene leading to decreased therapeutic effects; also, smoking cessation by a patient receiving propoxyphene chronically may increase its effects)
Opioid agonist analgesics, including alfentanil, fentanyl, and sufentanil (additive CNS depressant, respiratory depressant, and hypotensive effects may occur if two or more opioid agonist analgesics are used concurrently)
(pentazocine and nalbuphine may partially antagonize the analgesic and CNS depressant effects of opioid agonists)
(in patients who are not physically dependent on opioid agonists, concurrent use of butorphanol, nalbuphine, or pentazocine may result in additive side effects)
(in patients who are physically dependent on opioid agonists, nalbuphine and pentazocine may precipitate, and butorphanol will not prevent or attenuate, withdrawal symptoms)
Phenytoin, chronic use of, or
» Rifampin (these medications may increase methadone metabolism, probably via induction of hepatic microsomal enzyme activity, and may precipitate withdrawal symptoms in patients being treated for opioid dependence; methadone dosage adjustments may be necessary when phenytoin or rifampin therapy is initiated or discontinued)
» Zidovudine (morphine may competitively inhibit the hepatic glucuronidation and decrease the clearance of zidovudine; concurrent use should be avoided because the toxicity of either or both of these medications may be potentiated)

Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With diagnostic test results
Gastric emptying studies    (opioid analgesics delay gastric emptying, thereby invalidating test results )


Hepatobiliary imaging using technetium Tc 99m disofenin    (delivery of technetium Tc 99m disofenin to the small bowel may be prevented because opioid analgesics [except for butorphanol] may cause constriction of the sphincter of Oddi and increased biliary tract pressure; these actions result in delayed visualization and thus resemble obstruction of the common bile duct)

With physiology/laboratory test values
Cerebrospinal fluid (CSF) pressure    (may be increased; effect is secondary to respiratory depression–induced carbon dioxide retention)


Plasma amylase activity and
Plasma lipase activity    (may be increased because opioid analgesics [except butorphanol] can cause contractions of the sphincter of Oddi and increased biliary tract pressure; the diagnostic utility of determinations of these enzymes may be compromised for up to 24 hours after the medication has been given)


Serum alanine aminotransferase (ALT [SGPT]) and
Serum alkaline phosphatase and
Serum aspartate aminotransferase (AST [SGOT]) and
Serum bilirubin and
Serum lactate dehydrogenase (LDH)    (activity may be increased in patients receiving propoxyphene)


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:

For all opioid analgesic usage:
» Diarrhea associated with pseudomembranous colitis caused by cephalosporins, lincomycins (possibly including topical clindamycin), or penicillins or
» Diarrhea caused by poisoning, until toxic material has been eliminated from gastrointestinal tract    (opioid analgesics may slow elimination of toxic material, thereby worsening and/or prolonging the diarrhea)


» Respiratory depression, acute    (may be exacerbated)


For epidural or intrathecal administration:
» Any condition that precludes epidural or intrathecal administration, such as:
» Coagulation defects caused by anticoagulant therapy or hematologic disorders    (trauma to a blood vessel during administration may result in uncontrollable CNS or soft tissue hemorrhage)


» Infection at or near site of administration    (risk of spreading the infection into the CNS)


Risk-benefit should be considered when the following medical problems exist

For all opioid analgesics:
Abdominal conditions, acute    (diagnosis or clinical course may be obscured)


Allergic reaction to the opioid analgesic considered for use, history of
» Asthma, acute attack or
» Respiratory impairment or disease, chronic    (opioids may decrease respiratory drive and increase airway resistance in patients with these conditions)


Cardiac arrhythmias or
Convulsions, history of    (may be induced or exacerbated by opioids; meperidine and propoxyphene may be especially likely to induce or exacerbate convulsions; with meperidine, the proconvulsant activity of its metabolite normeperidine may be responsible )


Drug abuse or dependence, current or history of, including alcoholism, or
Emotional instability or
Suicidal ideation or attempts    (patient predisposition to drug abuse)


Gallbladder disease or gallstones    (opioids [except butorphanol] may cause biliary contraction)


Gastrointestinal tract surgery, recent    (opioids may alter gastrointestinal motility)


Head injury or
Increased intracranial pressure, pre-existing or
Intracranial lesions    (risk of respiratory depression and further elevation of cerebrospinal fluid pressure is increased; also, opioids may cause sedation and pupillary changes that may obscure clinical course of head injury)


Hepatic function impairment    (opioids metabolized in liver)


Hypothyroidism    (risk of respiratory depression and prolonged CNS depression is greatly increased)


» Inflammatory bowel disease, severe    (risk of toxic megacolon may be increased, especially with repeated dosing )


Prostatic hypertrophy or obstruction or
Urethral stricture or
Urinary tract surgery, recent    (opioids may cause urinary retention)


Renal function impairment    (increased risk of convulsions [with meperidine] or other adverse effects because opioids and/or their metabolites excreted primarily via kidneys; also, opioids may cause urinary retention)


Caution is also advised in administration to very young, elderly, or very ill or debilitated patients, who may be more sensitive to the effects, especially the respiratory depressant effects, of these medications.
For butorphanol, nalbuphine, or pentazocine only (in addition to those medical problems listed above):
Dependence on opioid agonist analgesics, current    (nalbuphine and pentazocine may precipitate, and butorphanol does not prevent occurrence of, withdrawal symptoms)


Hypertension    (butorphanol may increase blood pressure in these patients when used as presurgical medication)


» Myocardial infarction, acute    (pentazocine and butorphanol may increase cardiac work; effects of nalbuphine in patients with severely compromised cardiac function have not been fully evaluated)


For epidural or intrathecal administration (in addition to those medical problems listed above as applying to all opioid analgesics):
Dependence on opioid analgesics, current    (low doses of opioids administered via epidural or intrathecal injection will not prevent withdrawal symptoms from occurring in a physically dependent patient)



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Respiratory function    (monitoring recommended for at least 24 hours following epidural or intrathecal injection because delayed respiratory depression may occur up to 24 hours after administration via these routes)




Side/Adverse Effects

Table 4. Side/Adverse Effects ^*

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:	Legend: I=Butorphanol II=Codeine III=Hydrocodone IV=Hydromorphone				V=Levorphanol VI =Meperidine VII=Methadone			VIII=Morphine IX=Nalbuphine X=Opium			XI=Oxycodone XII=Oxymorphone XIII=Pentazocine XIV=Propoxyphene
	I	II	III	IV	V	VI	VII	VIII	IX	X	XI	XII	XIII	XIV
Medical attention needed
Allergic reaction (skin rash, hives, and/or itching †; swelling of face)	R (<1%)	L	R	R	R	R	R	L	L	R	R	R	L	L
Atelectasis; bronchospastic allergic reaction; laryngeal edema, allergic; laryngospasm, allergic; or respiratory depression ‡ (shortness of breath, slow or irregular breathing, troubled breathing)	R (<1%)	L	L	L	L	L	L	L	R (<1%)	R	R	L	L	U
CNS stimulation, paradoxical (unusual excitement or restlessness)—especially in children	R	L	R	R	R	R	R	R	R	R	R	R	R	R
Confusion §—may include delusions and feelings of depersonalization or unreality	R (<1%)	L	L	L	L	L	L	L	R (<1%)	L	R	L	R	R
Convulsions	U	R	R	U	U	L	U	U	U	U	U	U	R	L
Fast, slow, or pounding heartbeat	R (<1%)	L	L	L