No Increased Risk of Psychiatric Illness With Naltrexone

Pauline Anderson

December 20, 2018

Extended-release naltrexone (XR-NTX) and combination buprenorphine-naloxone (BP-NLX) have comparable outcomes for anxiety, depression, and insomnia in opioid-dependent patients aiming for abstinence, new research shows.

The new findings dispel the prevailing view that blocking opioid receptors with XR-NTX may trigger or worsen symptoms of anxiety, depression, or insomnia.

"We found that this myth, or this perceived opinion, is probably not correct," author Lars Tanum, MD, PhD, head of the addiction research group, and professor, Akershus University Hospital, Oslo, Norway, told Medscape Medical News.

"This is a very important message because this myth is quite deeply anchored in the medical community."

Tanum added that the results should not prevent switching from an opioid agonist to XR-NTX in patients who have overcome opioid addiction.

The study was published online yesterday in JAMA Psychiatry.

Prevalence of Psychiatric Illness High

Compared to the general population, patients with an opioid use disorder (OUD) have a higher prevalence of psychiatric disorders, including anxiety and depression, which are often accompanied by insomnia and negatively affect treatment outcomes.

Treatment with buprenorphine has been shown to reduce depression and anxiety in patients with an OUD. Extended release naltrexone is also promising, but has not been compared to an opioid agonist in terms of these outcomes.

Naltrexone and buprenorphine work differently to control addiction. Naltrexone is a full antagonist that blocks the mu, delta, and kappa opioid receptors.

Buprenorphine is a mu-opioid agonist although it also has a minor role as a kappa-opioid antagonist. Buprenorphine is often combined with smaller amounts of naloxone, an opioid antagonist, to prevent misuse.

The new two-part study included patients with dependence on opioids, mostly heroin, who were referred to a detoxification unit after screening. The investigators did not exclude patients with a psychiatric disorder except for those with severe mental illness.

After detoxification, 159 subjects, mean age about 36 years and about 28% women, were randomized to receive intramuscular injections of XR-NTX hydrochloride (380 mg) every 4 weeks, or daily sublingual BP-NLX.

The BP-NLX dose ranged from 4-24 mg/day, with a target of 16 mg/day. (The 4 mg tablet contains 4 mg buprenorphine and 1 mg naloxone; the 24 mg tablet contains 24 mg buprenorphine and 6 mg naloxone.)

The mean dose of buprenorphine was 11.2 mg/day. Tanum explained that this was lower than the target dose possibly because Norwegian patients "prefer to be on the lower side of what is considered a target dose."

The two groups were evenly distributed in terms of race/ethnicity. Four participants (two in each group) tested positive for HIV, and 86 participants (54.1%) had positive hepatitis C tests.

At week 12, 105 participants (66.0%) had completed the randomized portion of the study. There was no significant difference in treatment retention between the groups.

The primary endpoints were changes in anxiety, depression, and insomnia scores.

To assess anxiety and depression, researchers used the 25-item Hopkins Symptom Checklist (HSCL-25), on which questions are graded from 1 (not at all) to 4 (extremely).

No Between-Group Differences

To assess insomnia, they used the Insomnia Severity Index, a self-report questionnaire that measures numerous sleep parameters, including latency of sleep onset, sleep maintenance, and early morning awakening problems. The scoring is on a 5-point rating scale, with 0 indicating no problem and 4 a severe problem.

Results showed improvements in anxiety, depression, and insomnia within a few weeks of beginning either treatment.

Overall, there were no between-group differences in trends for anxiety and depression scores, but the insomnia score was significantly lower in the XR-NTX group (-0.32; −0.55 to −0.08; P = .008).

This difference remained significant after adjusting for multiple testing.

The authors noted that the estimated effect sizes were small, and the 95% confidence intervals (CIs) were relatively narrow for scores of anxiety (−0.14; 95% CI, −0.47 to 0.19), depression (−0.12; 95% CI, −0.45 to 0.21), and insomnia (−0.32; 95% CI, −0.65 to 0.02).

The associations between anxiety and depression scores and scores for drugs used illicitly (without prescriptions) were assessed for all participants together.

The anxiety score was not related to the use of heroin; however, mean anxiety scores increased significantly for 1 day’s extra use of other opiates, amphetamine, benzodiazepine, or cannabis.

The mean depression scores were significantly higher for 1 day's extra use of heroin, other opiates, benzodiazepine, amphetamine, and cannabis.

This part of the study was followed by a 36-week, open-label follow-up study in which participants chose to receive either of the two drugs. Most participants preferred XR-NTX.

Tanum speculated that subjects were attracted to naltrexone because they had already tried buprenorphine, which is freely available in Norway, and naltrexone represented "a new and unknown drug" that is not commercially available in Europe.

Surprise Finding

The results of the second part of the study were based on those who continued with XR-NTX and those who switched from BP-NLX to XR-NTX. The follow-up study included 109 participants, of which 58 completed the study (10 women and 48 men).

There were no overall differences in anxiety, depression, or insomnia scores between participants continuing with XR-NTX and those switching from BP-NLX to XR-NTX after week 12. Effect sizes were 0.04 for anxiety, -0.04 for depression, and 0.04 for insomnia scores.

Both higher mean anxiety scores, and higher mean depression scores, were significantly associated with 1 day’s extra use of heroin, benzodiazepine, amphetamine, and cannabis. There was no association between the use of other opioids and depression or anxiety scores.

Increases in anxiety and depression scores were significantly associated with higher insomnia scores (mean, 0.65; 95% CI, 0.41-0.84 and mean, 0.43; 0.30-0.57, respectively; P < .001), with no differences detected between treatment groups.

These correlations were "quite moderate," said Tanum. "The correlation was not so high that insomnia could be fully explained by the anxiety or depression symptoms," although these symptoms likely were a contributing factor to the insomnia score, he said.

Researchers believe there’s a complex interplay between use of illicit substances and sleep disturbances, anxiety, and depressive symptoms. The authors noted other studies reporting that opioid agonists have psychotropic effects on mood, sedation, and anxiety.

Sleep problems are regarded as a risk factor, a consequence, and a complication of both depression and opioid dependence.

Research suggests that depression and insomnia may share a common etiology or may simply coexist, and that depression and anxiety disorders independently affect sleep among users of illicit substances, said the authors.

Tanum acknowledged that the investigators were surprised that XR-NTX did not increase depression and anxiety symptoms.

"If you had asked me to make a bet, I would have bet $100 that these symptoms would have gotten worse."

The new results, he said, suggest that the prevailing view "is totally not based on science, but based more on clinical observations over time that have kind of run together and become clinical truth."

Tanum emphasized that in patients with moderate anxiety, depression or insomnia, "this should not be an obstacle or contraindication to give extended release naltrexone."

A limitation of the study was the use of self-report questionnaires to detect symptoms of depression, anxiety, and insomnia.

Another limitation is that reported drug use was not confirmed by testing urine samples in the follow-up period. However, the authors noted that the analyses performed in the randomized clinical trial part of the study showed a high correlation between the reported use of illicit substances and urine analysis results.

Valuable Study

Commenting on the findings for Medscape Medical News, Andrew J. Saxon, MD, Chair, American Psychiatric Association Council on Addiction Psychiatry and Professor, Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, said the findings have value in providing reassurance with respect to naltrexone.

There was concern that naltrexone could cause dysphoria, or a negative emotional state, he said. "The fact that the authors didn’t find any [dysphoria] is really positive in terms of not making us worry about using this medication in patients with opioid use disorder who may have psychiatric symptomatology."

However, Saxon said that the study subjects appear to be "the cream of the crop."

"I believe that the population being studied is a more motivated population, a more stable population, that is less psychiatrically impaired than the wider universe of people with opioid use disorder," said Saxon.

"So the study doesn’t help us understand what the effects of naltrexone might be on people who might have a harder time getting off opioids."

Total opioid abstinence is "very difficult to achieve," added Saxon. "Certainly in the US, we are lucky if we get 50% of the patients who start that to succeed with it."

Since the mean buprenorphine dose was "a little on the low side," results might have been better if the doses were higher, said Saxon.

For example, he "would not put too much weight on" the finding that naltrexone was superior to buprenorphine in terms of insomnia during the randomized portion of the study, he said.

However, study author Tanum doesn’t believe the lower-than- target buprenorphine dose affected outcomes.

"There was a range of doses among participants and there was no sign of any correlation between dose of buprenorphine and symptoms of anxiety, depression, or insomnia," he said.

Saxon noted that while the authors obtained information on psychiatric disorders, they didn’t include information on any relationship these diagnoses had on anxiety, depression, and insomnia symptoms.

Impact on Clinical Practice?

Asked about this, Tanum said the study did not show any correlation between psychiatric illnesses, including bipolar disorder, and outcomes for anxiety, depression, and insomnia.

Saxon added that it makes sense that symptoms of depression, anxiety, and insomnia improve when use of illicit substances is curtailed.

"That may not be a direct result of either of these medicines; it may be an indirect result of stopping the substance use," Saxon said.

Saxon doesn’t believe the new findings will have a "huge" impact on clinical practice.

"Which medication is used is largely driven by some social and economic factors," he said, "but also by the willingness of patients to undergo an episode of withdrawal and what facilities are available to do that."

Saxon noted that both buprenorphine and naltrexone are kappa antagonists. When activated, the kappa system tends to promote a negative mood, but when blocked, mood might improve. Researchers are exploring kappa antagonists as a possible treatment for depression, he said.

The study was supported by unrestricted grants from the Research Council of Norway and the Western Norway Regional Health Authority. Financial support was also received from the Norwegian Center for Addiction Research, University of Oslo, and Akershus University Hospital. Extended-release naltrexone was provided by Alkermes Inc in accordance with an investigator-initiated trial agreement. Dr Tanum has disclosed no relevant financial relationships. Dr Saxon reports he is an advisory board member for Alkermes Inc, and also reports that as section editor for drug use disorders at UpToDate, he receives royalties.

JAMA Psychiatry. Published online December 19, 2018. Full text

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