Receptor
Location
Effect
Δ (delta)
Brain (pontine nuclei, amygdala, olfactory bulb, deep cortex), peripheral sensory neurons
Slight analgesia, physical dependence, antidepressant
Κ (kappa)
Brain (hypothalamus, periaqueductal gray), spinal cord (substantia gelatinosa)
Analgesia, sedation, miosis, dysphoria
μ (mu)
Brain (cortex, thalamus, periaqueductal gray), spinal cord (substantia gelatinosa), peripheral sensory neurons, intestine
Respiratory depression, miosis, euphoria, decreased GI mobility, physical dependence
μ 1 : peripherally located – central interpretation of pain
μ 2 : CNS
μ 3 : vascular tissue, leukocytes
The various classes of opioids have varying ratios of receptor affinities or potency which result in characteristic clinical effects as well as differing analgesic responses to two different opioid classes despite an “equianalgesic” dose.
Across all opioid classes, side effects include drowsiness, changes in mood (which can include paradoxical excitation), miosis, respiratory depression, decreased gastrointestinal motility, nausea, vomiting, and autonomic dysregulation. Another side effect which may be beneficial in certain patients is depression of the medullary cough center.
A recent development is the FDA requirement of a formal risk evaluation and mitigation strategy (REMS) for commercializing and selling extended-release and long-acting opioid analgesics. This often entails REMS-compliant physician education programs and the patient counseling regarding the risks, safe use, storage, and disposal of opioids. Warnings common to all opioids include:
Abuse potential: risk factors for opioid abuse, addiction, or diversion should be considered.
Respiratory depression: life-threatening and fatal cases may occur even with recommended use, especially at the initiation of treatment or with dose increases.
Accidental exposure: accidental ingestion, especially by children, can be fatal.
Appropriate prescribing: opioids should be prescribed by health-care professionals knowledgeable in the use of potent opioids for chronic pain management.
The opioids in this chapter are generally classified as Schedule II controlled substances, which is the most restrictive classification that can be legally sold. Schedule II drugs have (1) a high potential for abuse, (2) a currently accept medical use, and (3) a potential for abuse with severe psychological or physical dependence. Some combination opioids (e.g., hydrocodone-acetaminophen) are Schedule III, which meet the first two criteria above but with a risk of “moderate to low physical dependence or high psychological dependence.” Schedule III drugs have slightly less restrictive rules for prescribing. Generally, unlike Schedule II drugs, Schedule III prescriptions can be faxed or phoned in to a pharmacy. Of note, some states do allow e-prescribing of Schedule II drugs.
Drug Class: Morphine (Oral)
Introduction
Morphine is the prototypic opioid, with a multitude of immediate- and extended-release formulations available. The class effects common across all opioids are discussed below.
Mechanism of Action
Although at higher doses morphine can activate the kappa and delta receptors, morphine is relatively selective for the mu receptor. Morphine undergoes first-pass hepatic metabolism and is metabolized through Phase 2 conjugative reactions by uridine diphosphate glucuronosyltransferase (UGT) enzymes. Five to fifteen percent of morphine is conjugated to morphine 6-glucuronide, which has analgesic activity and may accumulate in patients with renal failure. Excretion is largely in the urine and bile as morphine 3-glucuronide and 6-glucuronide metabolites. Peak analgesia from immediate-release morphine formulations occurs in about 60 min and can last 3–7 h.
Indications/Clinical Pearls
Morphine is indicated “for the treatment of moderate to severe pain, when a continuous around-the clock opioid analgesic is needed for an extended period of time” [3]. Long-acting formulations such as MS Contin and Kadian are “not intended for use as a prn analgesic” or for acute pain, including postoperative pain. The exception to this is if the patient is already taking chronic opioids and the postoperative pain is expected to persist for an extended period.
In addition to highly variable bioavailability, there is greater inter-patient variability in minimum effective concentration, which is influenced by age, prior exposure to opioids, and comorbidities. This means that it is difficult to predict the optimal dose for a particular patient ahead of time without titrating to analgesia versus side effects.
The half-life of morphine can be prolonged in patients with cirrhosis or hepatic dysfunction. Renal impairment can result in accumulation of the morphine 3-glucuronide and 6-glucuronide. The dosage should be decreased by up to 50 % in severe renal failure.
Morphine crosses placental membranes and is Pregnancy Category C and can be transmitted to infants via breast milk.
Dosing Options
There are numerous morphine-containing oral preparations such as:
Morphine sulfate is available in 15 and 30 mg tablets, to be taken every 3–4 h.
MS Contin, a long-acting formulation, is available in 15, 30, 60, 100, and 200 mg pills to be taken every 8–12 h.
Kadian is an extended-release capsule with morphine layered in an inert polymer that release morphine slowly. It is available in 10, 20, 30, 50, 60, 80, 100, and 200 mg capsules, to be taken daily.
Avinza is an extended-release capsule available in 30, 60, 90, and 120 mg and contains both immediate- and extended-release beads of morphine sulfate and is meant for once daily administration. The daily dose of Avinza should be limited to 1,600 mg/day as the quantity of fumaric acid contained in the preparation poses a risk of renal toxicity.
Drug Interactions
There is an increased risk of hypotension, respiratory depression, or severe sedation when morphine formulations are consumed with CNS depressants including benzodiazepines, other opioids, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and alcohol.
In particular, patients should be cautioned about concomitant alcohol consumption with extended-release preparations, as alcohol may cause the premature release of morphine.
Mixed agonist/antagonist analgesics (e.g., nalbuphine, butorphanol) can reduce the analgesic effect and may precipitate withdrawal symptoms in patients chronically taking morphine. Cimetidine may precipitate CNS toxicity, including apnea, confusion, muscle twitching, and seizures. MAO inhibitors may potentate the action of morphine; the FDA advises that morphine not be administered concomitantly or within 14 days of MAOI treatment [3].
Side Effects/Black Box Warnings
Morphine should be used in caution with acute abdominal conditions, such as proven or suspected paralytic ileus. In addition, given the risk of sphincter of Oddi spasm, morphine should be used with caution with biliary tract disease or pancreatitis.
Caution should also be used in administering morphine to patients with head injuries or increased intracranial pressure, as the vasodilation from morphine-induced carbon dioxide retention can elevate intracranial pressure.
Given the risk of respiratory depression, morphine should be given with caution to patients having conditions resulting in hypoxia or hypercapnia or decreased respiratory reserve. This includes asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, or CNS depression.
Extended-release preparations such as Avinza, which contain microcapsules, should not be chewed, crushed, or dissolved given a risk of a rapid release of a potentially fatal dose of morphine. In the case of parenteral abuse, the talc content can also cause tissue necrosis, pulmonary granulomas, endocarditis, and valvular injury.
Morphine-containing formulations may contain black box warnings regarding abuse potential, respiratory depression, and accidental ingestion. MS Contin and Kadian both contain black box warnings: “100 and 200 mg tablets are for use in opioid-tolerant patients only…these tablet strengths may cause fatal respiratory depression when administered to patients not previously exposed to opioids.” Avinza uniquely carries a specific black box warning that co-ingestion of alcohol can “result in the rapid release and absorption of a potentially fatal dose of morphine” (www.fda.gov).
Summary
Morphine is the opioid prototype, with broadly representative indications and side effects of this class of analgesics. It has immediate and extended-release preparations. Dosing should be adjusted for age and hepatic and renal dysfunction, and prescribers should be mindful of the potential for abuse, appropriate patient selection and dosage, and respiratory depression.
Drug Class: Oxymorphone
Introduction
Oxymorphone is a potent semisynthetic mu-opioid agonist. Initially designed to decrease the side effects as well as euphoria of morphine and heroin, it is an alternative opioid indicated for the treatment of moderate to severe pain.
Mechanism of Action
Oxymorphone is an agonist relatively selective for the mu-opioid receptor. It is more lipid soluble than morphine or oxycodone, resulting in rapid transfer across the blood-brain barrier. This produces a faster onset of analgesia and peak plasma concentration [4]. Oral bioavailability of oxymorphone is approximately 15–30 %. Oxymorphone is principally metabolized through Phase 2 glucuronidation and is renally excreted. Immediate-release oxymorphone has an analgesic onset of 30 min, peak analgesia at 60 min, and analgesic duration of 4–6 h. Extended-release oxymorphone (Opana ER) has a 12 h dosing interval, as the drug is released over time via a hydrophilic matrix.
Indications/Clinical Pearls
Immediate-release oxymorphone is indicated for moderate to severe acute pain, often in the setting of postsurgical pain, or as a rescue analgesic for cancer and chronic nonmalignant pain. Extended-release oxymorphone is indicated for the long-term treatment of chronic pain. Ten milligrams of oral oxymorphone is roughly equianalgesic to 30 mg of oral morphine. Given the low bioavailability of oxymorphone, the conversion ratio of parenteral to oral oxymorphone has been reported as 10:1 [4].
The half-life of oxymorphone can be prolonged in patients with cirrhosis or hepatic dysfunction, and appropriate dose reductions should be made. Oxymorphone is contraindicated in severe liver failure. Severe renal failure increase oxymorphone bioavailability by 65 %.
The elimination half-life is approximately 8 h (twice that of morphine and oxycodone) and steady state concentrations require 3 days of dosing of immediate relief oxymorphone [5]. Dose escalation should thus be undertaken judiciously.
Oxymorphone crosses placental membranes and is Pregnancy Category C. It has also been found in breast milk.
Dosing Options
Numorphan (suppository) is available in a 5 mg dose win a polyethylene glycol base to be taken every 4–6 h.
Opana IR (immediate-release) 5 and 10 mg PO every 4–6 h.
Opana ER (extended-release) 5, 7.5, 10, 15, 20, 30, 40 mg every12 h.
Drug Interactions
There is an increased risk of hypotension, respiratory depression, or severe sedation when oxymorphone formulations are consumed with CNS depressants including benzodiazepines, other opioids, tricyclic antidepressants, MAO inhibitors, and alcohol.
Patients should be cautioned about concomitant alcohol consumption with extended-release preparations such as Opana ER, as alcohol consumption may also cause the premature release of oxymorphone. Mixed agonist/antagonist analgesics (e.g., nalbuphine, butorphanol) can reduce the analgesic effect and may precipitate withdrawal symptoms in patients chronically taking oxymorphone.
In addition, oxymorphone use with anticholinergics may worsen urinary retention or severe constipation. Use with cimetidine may precipitate CNS toxicity, including apnea, confusion, muscle twitching, and seizures.
Side Effects/Black Box Warning
Oxymorphone side effects include those common to all opioids: CNS depression including sedation, confusion, and mood changes; GI effects including nausea, vomiting, and decreased motility; cardiovascular changes including orthostatic hypotension and increased pulmonary vascular resistance; respiratory depression; urinary retention; or itching.
Opana IR and Numorphan do not have any black box warnings. In addition to standard black box warnings about appropriate use, abuse potential, respiratory depression, and accidental exposure, Opana ER has a unique black box warning that alcohol “may result in an increase of plasma levels and potentially fatal overdose of oxymorphone” (www.fda.gov).
Summary
Oxymorphone is a potent semisynthetic mu-opioid agonist with typical opioid side effect for the treatment of moderate to severe pain. It has immediate as well as extended-release preparations. Dosing should be adjusted for age and hepatic and renal dysfunction, and alcohol use should be avoided with extended-release preparations.
Drug Class: Hydrocodone
Introduction
Hydrocodone is the most commonly prescribed drug in the United States, with almost 125 million prescriptions. It is most often sold as a combination, such as Vicodin which combines acetaminophen with hydrocodone. The potential for abuse, as well as the dangers of acetaminophen-induced hepatotoxicity of combination products, has lead to recent deliberations by the FDA regarding possibly reclassifying hydrocodone as Schedule II, rather than the current Schedule III [6].
Mechanism of Action
Hydrocodone is a mu-opiate receptor agonist. It is a metabolite of codeine, and Phase 1 hepatic metabolism occurs by cytochrome p450 2D6 (CYP2D6), to yield hydromorphone which is also biologically active. Hydrocodone and its metabolites undergo renal excretion. It has an analgesic onset of 15–60 min and duration of 4–6 h.
Clinical Pearls/Indications
Hydrocodone is indicated for the relief of moderate to moderately severe pain. Ten to fifteen milligrams of hydrocodone is approximately equianalgesic to 10 mg of oral morphine. It should be used with caution or in reduced dosage in elderly patients or those with hepatic or renal dysfunction.
Care must be given when combination drugs include an acetaminophen component because patients who take more medication than prescribed may have a risk not only of opioid-related side effects but of acetaminophen-induced hepatotoxicity as well. The most recent FDA recommendation is no greater than 3,250 mg of acetaminophen a day, although 3,000 mg is a commonly presented maximum daily dose by acetaminophen manufacturers [7].
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Pharmacokinetics, Pharmacodynamics, and Physical Properties of Inhalational Agents
Novel Psychoactive Substances: Synthetic Cathinones and Cannabinoid Receptor Agonists
New Vistas in Anesthetics, IV Induction Agents
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