Adverse effects naltrexone

At the doses used, there is blockage of the effects of as much as 25 mg of injected heroin. Toxicity in heroin addicts is low, but some reported subtle adverse effects of naltrexone such as decreased energy (Hollister et al. 1981). Nonaddicted obese subjects have been known to develop markedly elevated transaminase levels at doses of 300 mg/day (Mitchell et al. 1987). The inference has been drawn that high doses are potentially hepatotoxic (Pfohl et al. 1986), and the drug is contraindicated in liver failure or acute hepatitis. 

The intoxicating effects of opioids appear to be due to their action as agonists on mu (p) receptors of the opioid neurotransmitter system. Competitive p opioid antagonists such as naloxone and naltrexone acutely reverse many of the adverse effects of opioids. To date we do not have specific antagonists for most other abused substances, so rapid pharmacologic reversal of intoxication is usually not possible. 

Dose-response data indicate that 2 grams per day was optimal. In addition, this agent demonstrates an excellent safety profile, with loose stools or diarrhea being the only adverse effects reported more often than with placebo. Other data indicate that this agent can be safely administered concurrently with disulfiram or naltrexone. 

Efficacy and clinical use Naltrexone (Crabtree, 1984 Gonzalez and Brogden, 1988) is a pure opioid antagonist and has no analgesic activity. It is used for the treatment of opioid adverse effects, for opioid detoxification and as maintenance treatment for former addicts to avoid a relapse. In chronic opioid users, naltrexone may precipitate an acute withdrawal reaction. 

The neurotoxic adverse effects of interferon alfa may be mediated by an action at opioid receptors, and naltrexone may antagonize some of this (SEDA-20,83). Pruritus, probably mediated via enkephalins and opioids, may also be antagonized by naltrexone (SEDA-22,104). 

When naltrexone was used in the treatment of alcohol dependence, 5-10% of patients discontinued treatment because of adverse effects (SEDA-20, 83). 

A systematic review and meta-analysis of seven doubleblind, randomized, placebo-controlled outpatient studies of naltrexone used in the treatment of alcohol dependence between 1976 and 2001 has shown that naltrexone was no more toxic than placebo and was not associated with a significantly greater number of withdrawals because of adverse effects (1). Naltrexone was more effective than placebo in reducing relapses to heavy... 

To examine the relation between adverse effects profiles, study retention, and treatment outcomes in alcohol-dependent individuals receiving naltrexone for relapse prevention, 92 subjects had their adverse effects monitored weekly and categorized as either neuropsychiatric or gastrointestinal (3). The neuropsychiatric adverse effects had little effect on medication compliance but reduced the length of study retention. In contrast, the gastrointestinal adverse effects significantly affected medication compliance but not study retention. 

In an open, single-blind, randomized study, naltrexone (50 mg/day) and acamprosate (1665-1998 mg/day) were used for 1 year by 157 recently detoxified alcohol-dependent men with moderate dependence (4). The time to first relapse was 63 days (naltrexone) and 42 days (acamprosate) after 1 year, 41% of those given naltrexone and 17% of those given acamprosate had not relapsed. Adverse effects were more common with naltrexone and were worse during the first 2 weeks of treatment. They included nausea (25 versus 4%), abdominal pain (23 versus 4%), drowsiness (35 versus 2%), headache (13 versus 6%), and nasal congestion (23 versus 7%). 

The Health Technology Board of Scotland has concluded that in people with alcohol dependence, naltrexone reduces drinking (5). In a multicenter, double-blind, placebo-controlled, 12-week study of naltrexone 50 mg/day in 202 patients with alcohol dependence naltrexone was well tolerated, with few adverse effects abdominal pain (8.6%), headache (7.5%), nausea (6.5%), and dizziness (5.4%) there were no changes in liver function tests (6). However, those who took naltrexone did not have significant improvements in drinking history or fewer relapses. 

Gastrointestinal adverse effects of naltrexone were also observed in 183 alcohol-dependent individuals who received either naltrexone or nefazodone (15). These adverse effects predicated early termination of naltrexone used to treat alcohol dependence (16). 

Reversible hepatocellular injury has been reported with naltrexone in doses of up to 300 mg/day, which is five times that usually used for opioid blockade (SED-11, 147) (17). Five of twenty-six patients treated with naltrexone for obesity developed raised serum transaminase activities after 3-8 weeks of treatment. In another study in which 60 obese subjects received naltrexone for 8 weeks, there were abnormal liver function tests in six patients. Three patients failed to complete the course. Nausea and vomiting occurred within the first 24 hours of treatment but responded to a reduction in dose. There were also changes in mentation such as decreased mental acuity, depression, and anxiety, all of which resolved after withdrawal. This is significant, as adverse effects from naltrexone have previously been attributed to mild physical withdrawal syndromes. 

Oncken C, Van Kirk J, Kranzler HR. Adverse effects of oral naltrexone analysis of data from two clinical trials. Psychopharmacology (Berl) 2001 154(4) 397 02. 

FIG. 5. The number of errors on an inclined plane response flexibility problem (Thompson et al 1990) is shown for the same groups of animals as seen in Fig. 4. Saline-treated controls made the fewest errors. Animals exposed to the neurotoxin MAM were slower to abandon a previously learned solution to try new routes to food. However, animals treated postnatally with naltrexone, an opiate receptor antagonist reported to induce dendritic arborization and spine formation, showed performance similar to controls. Decreases in neuron number, such as seen with MAM exposure prenatally, have adverse effects on tests of rat intelligence. Treatments that induce dendritic arborization and synapse formation can ameliorate these deficits. The ability to modify brain structure permits direct testing of the causal role of variation in brain structure and behavioural performance. 

A double-blind crossover study of naltrexone (1 mg/kg/day, 2 weeks) in 13 children with autistic disorder found significant improvement over placebo with respect to both parent and teacher ratings on the CGI scale, the impulsivity-hyperactivity factor of the Connor Rating Scale, and restlessness on the Naltrexone Side Effect Rating Scale. Overall, 8 of the 13 subjects demonstrated modest improvement during the naltrexone treatment phase. No significant adverse effects of naltrexone were observed, although the bitter taste of naltrexone was a problem for some children. 

Naltrexone modestly increases the rate and extent of acamprosate absorption. There is no pharmacokinetic interaction between acamprosate and alcohol or diazepam. Disulflram does not alter the pharmacokinetics of acamprosate, and acamprosate does not alter the pharmacokinetics of imipramine. The combination of acamprosate and barbiturates, meprobamate, or oxazepam does not appear to increase the risk of adverse effects. 

Combined morphine/naltrexone capsules have shown comparable analgesia, adverse effects and bioequivalence to a similar morphine sulfate extended-release capsule product (Kadian ) with regard to rate and extent of plasma morphine absorption [8]. In the clinical efficacy trial in patients with pain due to osteoarthritis, change in the weekly BPI average pain score was statistically significantly superior for those treated with Embeda as compared to placebo. A review of the Subjective Opiate Withdrawal Scales (SOWS)... 

Abboud TK, Afrasiabi A, Davidson J, Zhu J, Reyes A, Khoo N, Steffens Z. Prophylactic oral naltrexone with epidural morphine effect on adverse reactions and ventilatory responses to carbon dioxide. Anesthesiology 1990 72(2) 233-7. 

Naltrexone 100 mg/day-I-sertraline 200 mg/day was more effective than either drug alone in depression and alcohol abstinence/ delay before relapse. Alcohol-dependent depressed patients (n = 170) were randomly assigned to four groups naltrexone only, sertraline only, naltrexone-I-sertraline, and placebo. All received weekly cognitive behavioral therapy. The rate of adverse events was lower in the combination treatment group (12%) than in the other groups (naltrexone 27%, sertraline 38%, placebo 28%) however, more subjects withdrew seven patients compared with two, four, and one in the naltrexone, sertraline, and placebo groups respectively [213. ... 

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