During two randomized, double-blind placebo-controlled 12-week trials to evaluate the efficacy of
naltrexone hydrochloride as an adjunctive treatment of alcohol dependence, most patients tolerated
naltrexone hydrochloride well. In these studies, a total of 93 patients received naltrexone hydrochloride
at a dose of 50 mg once daily. Five of these patients discontinued naltrexone hydrochloride because of
nausea. No serious adverse events were reported during these two trials.
While extensive clinical studies evaluating the use of naltrexone hydrochloride in detoxified, formerly
opioid-dependent individuals failed to identify any single, serious untoward risk of naltrexone
hydrochloride use, placebo-controlled studies employing up to five fold higher doses of naltrexone
hydrochloride (up to 300 mg per day) than that recommended for use in opiate receptor blockade have
shown that naltrexone hydrochloride causes hepatocellular injury in a substantial proportion of patients
exposed at higher doses (see WARNINGS and PRECAUTIONS, Laboratory Tests).
Aside from this finding, and the risk of precipitated opioid withdrawal, available evidence does not
incriminate naltrexone hydrochloride, used at any dose, as a cause of any other serious adverse reaction
for the patient who is “opioid-free.” It is critical to recognize that naltrexone hydrochloride can
precipitate or exacerbate abstinence signs and symptoms in any individual who is not completely free of
Patients with addictive disorders, especially opioid addiction, are at risk for multiple numerous adverse
events and abnormal laboratory findings, including liver function abnormalities. Data from both
controlled and observational studies suggest that these abnormalities, other than the dose-related
hepatotoxicity described above, are not related to the use of naltrexone hydrochloride.
Among opioid-free individuals, naltrexone hydrochloride administration at the recommended dose has
not been associated with a predictable profile of serious adverse or untoward events. However, as
mentioned above, among individuals using opioids, naltrexone hydrochloride may cause serious
withdrawal reactions (see CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION).
Reported Adverse Events
Naltrexone hydrochloride has not been shown to cause significant increases in complaints in placebocontrolled
trials in patients known to be free of opioids for more than 7 to 10 days. Studies in alcoholic
populations and in volunteers in clinical pharmacology studies have suggested that a small fraction of
patients may experience an opioid withdrawal-like symptom complex consisting of tearfulness, mild
nausea, abdominal cramps, restlessness, bone or joint pain, myalgia, and nasal symptoms. This may
represent the unmasking of occult opioid use, or it may represent symptoms attributable to naltrexone. A
number of alternative dosing patterns have been recommended to try to reduce the frequency of these
In an open label safety study with approximately 570 individuals with alcoholism receiving naltrexone
hydrochloride, the following new-onset adverse reactions occurred in 2% or more of the patients:
nausea (10%), headache (7%), dizziness (4%), nervousness (4%), fatigue (4%), insomnia (3%), vomiting
(3%), anxiety (2%) and somnolence (2%).
Depression, suicidal ideation, and suicidal attempts have been reported in all groups when comparing
naltrexone, placebo, or controls undergoing treatment for alcoholism.
||RATE RANGES OF NEW ONSET EVENTS
||0 to 15%
||0 to 17%
||0 to 1%
||0 to 3%
Although no causal relationship with naltrexone hydrochloride is suspected, physicians should be
aware that treatment with naltrexone hydrochloride does not reduce the risk of suicide in these patients
The following adverse reactions have been reported both at baseline and during the naltrexone
hydrochloride clinical trials in opioid addiction at an incidence rate of more than 10%:
Difficulty sleeping, anxiety, nervousness, abdominal pain/cramps, nausea and/or vomiting, low energy,
joint and muscle pain, and headache.
The Incidence Was Less Than 10% For
Loss of appetite, diarrhea, constipation, increased thirst, increased energy, feeling down, irritability,
dizziness, skin rash, delayed ejaculation, decreased potency, and chills.
The Following Events Occurred In Less Than 1% Of Subjects
Respiratory: Nasal congestion, itching, rhinorrhea, sneezing, sore throat, excess mucus or phlegm, sinus trouble,
heavy breathing, hoarseness, cough, shortness of breath.
Cardiovascular: Nose bleeds, phlebitis, edema, increased blood pressure, non-specific ECG changes, palpitations,
Gastrointestinal: Excessive gas, hemorrhoids, diarrhea, ulcer.
Musculoskeletal: Painful shoulders, legs or knees; tremors, twitching.
Genitourinary: Increased frequency of, or discomfort during, urination; increased or decreased sexual interest.
Dermatologic: Oily skin, pruritus, acne, athlete’s foot, cold sores, alopecia.
Psychiatric: Depression, paranoia, fatigue, restlessness, confusion, disorientation, hallucinations, nightmares, bad
Special senses: Eyes blurred, burning, light sensitive, swollen, aching, strained; ears- “clogged”, aching, tinnitus.
General: Increased appetite, weight loss, weight gain, yawning, somnolence, fever, dry mouth, head “pounding”,
inguinal pain, swollen glands, “side” pains, cold feet, “hot spells.”
Data collected from postmarketing use of naltrexone hydrochloride show that most events usually occur
early in the course of drug therapy and are transient. It is not always possible to distinguish these
occurrences from those signs and symptoms that may result from a withdrawal syndrome. Events that
have been reported include anorexia, asthenia, chest pain, fatigue, headache, hot flushes, malaise,
changes in blood pressure, agitation, dizziness, hyperkinesia, nausea, vomiting, tremor, abdominal pain,
diarrhea, palpitations, myalgia, anxiety, confusion, euphoria, hallucinations, insomnia, nervousness,
somnolence, abnormal thinking, dyspnea, rash, increased sweating, vision abnormalities and idiopathic
In some individuals the use of opioid antagonists has been associated with a change in baseline levels
of some hypothalamic, pituitary, adrenal, or gonadal hormones. The clinical significance of such
changes is not fully understood.
Adverse events, including withdrawal symptoms and death, have been reported with the use of
naltrexone hydrochloride in ultra rapid opiate detoxification programs. The cause of death in these
cases is not known (see WARNINGS).
In a placebo controlled study in which naltrexone hydrochloride was administered to obese subjects at a
dose approximately five-fold that recommended for the blockade of opiate receptors (300 mg per day),
19% (5/26) of naltrexone hydrochloride recipients and 0% (0/24) of placebo-treated patients developed
elevations of serum transaminases (i.e., peak ALT values ranging from 121 to 532; or 3 to 19 times their
baseline values) after three to eight weeks of treatment. The patients involved were generally clinically
asymptomatic, and the transaminase levels of all patients on whom follow-up was obtained returned to
(or toward) baseline values in a matter of weeks.
Transaminase elevations were also observed in other placebo controlled studies in which exposure to
naltrexone hydrochloride at doses above the amount recommended for the treatment of alcoholism or
opioid blockade consistently produced more numerous and more significant elevations of serum
transaminases than did placebo. Transaminase elevations occurred in 3 of 9 patients with Alzheimer's
Disease who received naltrexone hydrochloride (at doses up to 300 mg/day) for 5 to 8 weeks in an
open clinical trial.