12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Morphine is a full opioid agonist and is relatively selective for the mu-opioid receptor, although it can bind to other opioid receptors at higher doses. The principal therapeutic action of morphine is analgesia. Like all full opioid agonists, there is no ceiling effect for analgesia with morphine. Clinically, dosage is titrated to provide adequate analgesia and may be limited by adverse reactions, including respiratory and CNS depression.
The precise mechanism of the analgesic action is unknown. However, specific CNS opioid receptors for endogenous compounds with opioid-like activity have been identified throughout the brain and spinal cord and are thought to play a role in the analgesic effects of this drug.
Effects on the Central Nervous System
Morphine produces respiratory depression by direct action on brain stem respiratory centers. The respiratory depression involves a reduction in the responsiveness of the brain stem respiratory centers to both increases in carbon dioxide tension and electrical stimulation.
Morphine causes miosis, even in total darkness. Pinpoint pupils are a sign of opioid overdose but are not pathognomic (e.g., pontine lesions of hemorrhagic or ischemic origins may produce similar findings). Marked mydriasis rather than miosis may be seen due to hypoxia in overdose situations.
Both early and late respiratory depression (up to 24 hours post dosing) have been reported following neuraxial administration. Circulation of the spinal fluid may also result in high concentrations of morphine reaching the brain stem directly.
Effects on the Gastrointestinal Tract and Other Smooth Muscle
Morphine causes a reduction in motility associated with an increase in smooth muscle tone in the antrum of the stomach and duodenum. Digestion of food in the small intestine is delayed and propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased, while tone may be increased to the point of spasm, resulting in constipation. Other opioid-induced effects may include a reduction in biliary and pancreatic secretions, spasm of sphincter of Oddi, and transient elevations in serum amylase.
Effects on the Cardiovascular System
Morphine produces peripheral vasodilation, which may result in orthostatic hypotension or syncope. Manifestations of histamine release and/or peripheral vasodilation may include pruritus, flushing, red eyes, sweating, and/or orthostatic hypotension.
Effects on the Endocrine System
Opioids inhibit the secretion of adrenocorticotropic hormone (ACTH), cortisol, and luteinizing hormone (LH) in humans [See Adverse Reactions (6)]. They also stimulate prolactin, growth hormone (GH) secretion, and pancreatic secretion of insulin and glucagon.
Chronic use of opioids may influence the hypothalamic-pituitary-gonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date [see Adverse Reactions (6)].
Effects on the Immune System
Opioids have been shown to have a variety of effects on components of the immune system in in vitro and animal models. The clinical significance of these findings is unknown. Overall, the effects of opioids appear to be modestly immunosuppressive.
Concentration – Efficacy Relationships
The minimum effective analgesic concentration will vary widely among patients, especially among patients who have been previously treated with potent agonist opioids. The minimum effective analgesic concentration of morphine for any individual patient may increase over time due to an increase in pain, the development of a new pain syndrome, and/or the development of analgesic tolerance [See Dosage and Administration (2.1)].
Concentration – Adverse Reaction Relationships
There is a relationship between increasing morphine plasma concentration and increasing frequency of dose-related opioid adverse reactions such as nausea, vomiting, CNS effects, and respiratory depression. In opioid-tolerant patients, the situation may be altered by the development of tolerance to opioid-related adverse reactions [See Dosage and Administration (2.1, 2.2, 2.6)].
Morphine has an apparent volume of distribution ranging from 1.0 to 4.7 L/kg after intravenous dosage. Protein binding is low, about 36%, and muscle tissue binding is reported as 54%. A blood-brain barrier exists, and when morphine is introduced outside of the CNS (e.g., intravenously), plasma concentrations of morphine remain higher than the corresponding CSF morphine levels. Conversely, when morphine is injected into the intrathecal space, it diffuses out into the systemic circulation slowly, accounting for the long duration of action of morphine administered by this route.
Morphine has a total plasma clearance which ranges from 0.9 to 1.2 L/kg/h (liters/kilogram/hour) in postoperative patients, but shows considerable interindividual variation. The major pathway of clearance is hepatic glucuronidation to morphine-3-glucuronide, which is pharmacologically inactive. The major excretion path of the conjugate is through the kidneys, with about 10% in the feces. Morphine is also eliminated by the kidneys, 2 to 12% being excreted unchanged in the urine. Terminal half-life is commonly reported to vary from 1.5 to 4.5 hours, although the longer half-lives were obtained when morphine levels were monitored over protracted periods with very sensitive radioimmunoassay methods. The accepted elimination half-life in normal subjects is 1.5 to 2 hours.
Morphine, injected into the epidural space, is rapidly absorbed into the general circulation. Absorption is so rapid that the plasma concentration-time profiles closely resemble those obtained after intravenous or intramuscular administration. Peak plasma concentrations averaging 33 to 40 ng/mL (range 5 to 62 ng/mL) are achieved within 10 to 15 minutes after administration of 3 mg of morphine. Plasma concentrations decline in a multiexponential fashion. The terminal half-life is reported to range from 39 to 249 minutes (mean of 90 ± 34.3 min) and, though somewhat shorter, is similar in magnitude as values reported after intravenous and intramuscular administration (1.5 to 4.5 h). CSF concentrations of morphine, after epidural doses of 2 to 6 mg in postoperative patients, have been reported to be 50 to 250 times higher than corresponding plasma concentrations. The CSF levels of morphine exceed those in plasma after only 15 minutes and are detectable for as long as 20 hours after the injection of 2 mg of epidural morphine. Approximately 4% of the dose injected epidurally reaches the CSF. This corresponds to the relative minimum effective epidural and intrathecal doses of 5 mg and 0.25 mg, respectively. The disposition of morphine in the CSF follows a biphasic pattern, with an early half-life of 1.5 h and a late phase half-life of about 6 h. Morphine crosses the dura slowly, with an absorption half-life across the dura averaging 22 minutes. Maximum CSF concentrations are seen 60 to 90 minutes after injection. Minimum effective CSF concentrations for postoperative analgesia average 150 ng/mL (range < 1–380 ng/mL).
The intrathecal route of administration circumvents meningeal diffusion barriers and, therefore, lower doses of morphine produce comparable analgesia to that induced by the epidural route. After intrathecal bolus injection of morphine, there is a rapid initial distribution phase lasting 15 to 30 minutes and a half-life in the CSF of 42 to 136 min (mean 90 ± 16 min). Derived from limited data, it appears that the disposition of morphine in the CSF, from 15 minutes postintrathecal administration to the end of a six-hour observation period, represents a combination of the distribution and elimination phases. Morphine concentrations in the CSF averaged 332 ± 137 ng/mL at 6 hours, following a bolus dose of 0.3 mg of morphine. The apparent volume of distribution of morphine in the intrathecal space is about 22 ± 8 mL.
Time-to-peak plasma concentrations, however, are similar (5 to 10 min) after either epidural or intrathecal bolus administration of morphine. Maximum plasma morphine concentrations after 0.3 mg intrathecal morphine have been reported from < 1 to 7.8 ng/mL. The minimum analgesic morphine plasma concentration during Patient-Controlled Analgesia (PCA) has been reported as 20 to 40 ng/mL, suggesting that any analgesic contribution from systemic redistribution would be minimal after the first 30 to 60 minutes with epidural administration and virtually absent with intrathecal administration of morphine.