Page 585 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 31 Opioid Agonists & Antagonists 571

Pharmacodynamics dosage can often eliminate the itching, nausea, and vomiting
while sparing the analgesia. For this purpose, oral naloxone, and
When given in the absence of an agonist drug, these antagonists modified analogs of naloxone and naltrexone, have been approved
are almost inert at doses that produce marked antagonism of ago- by the FDA. These include methylnaltrexone bromide for
nist opioid effects. the treatment of constipation in patients with opioid-induced
When given intravenously to a morphine-treated subject, the constipation (OIC) with chronic noncancer pain and late-stage
antagonist completely and dramatically reverses the opioid effects advanced illness and naloxegol and alvimopan for the treatment
within 1–3 minutes. In individuals who are acutely depressed by of postoperative ileus following bowel resection surgery. Methyln-
an overdose of an opioid, the antagonist effectively normalizes altrexone has a quaternary amine preventing it from crossing the
respiration, level of consciousness, pupil size, bowel activity, and blood-brain barrier. Naloxegol is pegylated naloxone, which limits
awareness of pain. In dependent subjects who appear normal penetration into the CNS and through peripheral μ-antagonism
while taking opioids, naloxone or naltrexone almost instanta- mitigates constipation. Alvimopan has a high affinity for periph-
neously precipitates an abstinence syndrome. eral μ receptors and does not impair the central effects of μ-opioid
There is no tolerance to the antagonistic action of these agents, agonists. The principal mechanism for the selective therapeutic
nor does withdrawal after chronic administration precipitate an effect of these agents is peripheral enteric μ-receptor antagonism
abstinence syndrome.
with minimal CNS penetration.
Because of its long duration of action, naltrexone has been
Clinical Use proposed as a maintenance drug for addicts in treatment pro-
Naloxone is a pure antagonist and is preferred over older weak grams. A single dose given on alternate days blocks virtually all
agonist-antagonist agents that had been used primarily as antago- of the effects of a dose of heroin. It might be predicted that this
nists, eg, nalorphine and levallorphan. approach to rehabilitation would not be popular with a large per-
The major application of naloxone is in the treatment of centage of drug users unless they are motivated to become drug-
acute opioid overdose (see also Chapter 58). It is very important free. A related use is in combination with morphine sulfate in a
that the relatively short duration of action of naloxone be borne in controlled-release formulation (Embeda) in which 20–100 mg
mind, because a severely depressed patient may recover after a single of morphine is slowly released over 8–12 hours or longer for the
dose of naloxone and appear normal, only to relapse into coma after control of prolonged postoperative pain. Naltrexone, 0.4–4 mg, is
1–2 hours. sequestered in the center of the formulation pellets and is present
The usual initial dose of naloxone is 0.1–0.4 mg intravenously to prevent the misuse of the morphine (by grinding and extraction
for life-threatening respiratory and CNS depression. Maintenance of the morphine from the capsules).
is with the same drug, 0.4–0.8 mg given intravenously, and There is evidence that naltrexone decreases the craving for
repeated whenever necessary. In using naloxone in the severely alcohol in chronic alcoholics by increasing baseline β-endorphin
opioid-depressed newborn, it is important to start with doses of release, and it has been approved by the FDA for this purpose (see
5–10 mcg/kg and to consider a second dose of up to a total of Chapter 23). Naltrexone also facilitates abstinence from nicotine
25 mcg/kg if no response is noted. (cigarette smoking) with reduced weight gain. In fact, a combina-
Low-dose naloxone (0.04 mg) has an increasing role in the tion of naltrexone plus bupropion (Chapter 16) may also offer an
treatment of adverse effects that are commonly associated with effective and synergistic strategy for weight loss.
intravenous or epidural opioids. Careful titration of the naloxone