The usual initial dose of naloxone is 0.1–0.4 mg intravenously for life-threatening respiratory and CNS depression. Maintenance is with the same drug, 0.4–0.8 mg given intravenously, and repeated whenever necessary. In using naloxone in the severely opioid-depressed newborn, it is important to start with doses of 5–10 mcg/kg and to consider a second dose of up to a total of 25 mcg/kg if no response is noted.
Low-dose naloxone (0.04 mg) has an increasing role in the treatment of adverse effects that are commonly associated with intravenous or epidural opioids. Careful titration of the naloxone dosage can often eliminate the itching, nausea, and vomiting while sparing the analgesia. For this purpose, oral naloxone, and modified analogs of naloxone and naltrexone, have been approved by the FDA. These include methylnaltrexone bromide for the treatment of constipation in patients with opioid-induced constipation (OIC) with chronic noncancer pain and late-stage advanced illness and naloxegol and alvimopan for the treatment of postoperative ileus following bowel resection surgery. Methylnaltrexone has a quaternary amine preventing it from crossing the blood-brain barrier. Naloxegol is pegylated naloxone, which limits penetration into the CNS and through peripheral μ-antagonism mitigates constipation. Alvimopan has a high affinity for peripheral μ receptors and does not impair the central effects of μ-opioid agonists. The principal mechanism for the selective therapeutic effect of these agents is peripheral enteric μ-receptor antagonism with minimal CNS penetration.
Because of its long duration of action, naltrexone has been proposed as a maintenance drug for addicts in treatment programs. A single dose given on alternate days blocks virtually all of the effects of a dose of heroin. It might be predicted that this approach to rehabilitation would not be popular with a large percentage of drug users unless they are motivated to become drug-free. A related use is in combination with morphine sulfate in a controlled-release formulation (Embeda) in which 20–100 mg of morphine is slowly released over 8–12 hours or longer for the control of prolonged postoperative pain. Naltrexone, 0.4–4 mg, is sequestered in the center of the formulation pellets and is present to prevent the misuse of the morphine (by grinding and extraction of the morphine from the capsules).
There is evidence that naltrexone decreases the craving for alcohol in chronic alcoholics by increasing baseline β-endorphin release, and it has been approved by the FDA for this purpose (see Chapter 23). Naltrexone also facilitates abstinence from nicotine (cigarette smoking) with reduced weight gain. In fact, a combination of naltrexone plus bupropion (Chapter 16) may also offer an effective and synergistic strategy for weight loss.
• Hydromorphone, oxymorphone: Like morphine in efficacy, but higher potency • Meperidine:
Strong agonist with anticholinergic effects • Oxycodone: • Sufentanil, alfentanil, remifentanil: Like fentanyl but shorter durations of action anesthesia (fentanyl, morphine) except methadone, 4–6 h
Toxicity: Respiratory depression
Poorly understood but strong and partial μ agonists are also effective antitussives