Interaction between buprenorphine TDS and antidepressants

concomitant drug use which had an impact on the tolerability of buprenorphine TDS.

Even though relatively few individuals who received buprenorphine used

antidepressants (n=14), we found that those who did were at the highest risk of discontinuation of treatment due to adverse events. When analyses were stratified on antidepressant use, those who did not use antidepressants did not have significantly increased risk of discontinuation during buprenorphine treatment compared with placebo, as illustrated in Figure 6. Even though the number of participants who received active treatment and did not use antidepressants was higher (n=30), we did not find a statistically significant increase in discontinuation risk in this group compared with antidepressant nonusers who received placebo (n=18; Figure 6). In comparison, the 14 individuals who used antidepressants and received buprenorphine had a large, statistically significant risk increase compared with those who used antidepressants and received placebo (n=27; Figure 6).

Although subgroup analyses must be interpreted with caution due to low sample size, this highly significant effect suggests that a drug interaction between antidepressants and buprenorphine, rather than adverse effects of buprenorphine alone, may be the mechanism behind the low tolerability of buprenorphine TDS observed in the DEP.PAIN.DEM trial. An interaction between buprenorphine and antidepressant drugs has not previously been specifically described in the literature.

Of those who received buprenorphine and used antidepressants, seven used escitalopram, five used mirtazapine, and two used mianserin. Within each antidepressant group, four, three, and two participants, respectively, had adverse events which led to premature discontinuation of treatment.

Combinations of drugs with either serotonergic or anticholinergic activity are known to cause clinically relevant interactions in frail elderly people. Antidepressants of the SSRI class may cause serotonin toxicity, particularly in combination with other drugs that cause increased central serotonin levels.²²⁶

Escitalopram is an SSRI with strong serotonergic properties, and the most frequent adverse effects include diarrhoea, dizziness, xerostomia, fatigue, headache, nausea, sweating, sedation, and tremor.^227,228

Figure 6. Discontinuation risk stratified by antidepressant use

Cox regression, adjusted for age and sex. CI, confidence interval.

Mirtazapine and mianserin are tetracyclic antidepressants (TeCAs) which act as NaSSAs. Mirtazapine acts as an antagonist on the α2-receptors of the adrenergic system, as well as on several 5-HT receptor subtypes, thereby enhancing serotonergic activity.²²⁹ Dry mouth, sedation, and increases in appetite and body weight are the most common adverse effects.²²⁹ Mianserin has a similar pattern of activity.²³⁰ A potential mechanism for the observed interaction may be additive or synergistic effects of buprenorphine and antidepressants on sedation, as all the types of

antidepressants used may cause sedation. This is also supported by reports of increased sedation as the most frequent adverse effect of buprenorphine in the DEP.PAIN.DEM trial. However, we did not find that sedation or somnolence was reported more frequently in those who received buprenorphine and used

antidepressants compared with those who did not (Pearson χ²-test, p=0.913).

Another potential explanation for the observed interaction may be the antagonistic effects of buprenorphine on the opioid κ-receptor. Activation of the κ-receptor causes adverse effects such as hallucination, dysphoria, increased anxiety, and aversion, in addition to analgesic effects.114,157,158 In contrast to full opioid agonists such as morphine and oxycodone which activate the receptor, buprenorphine acts as a κ-receptor antagonist and is therefore associated with a lower risk of treatment-induced dysphoria. Antidepressants exert their effects on the monoamine neurotransmitter systems, and an emerging body of evidence suggests that κ-receptors also modulate dopaminergic and serotonergic signalling.²³¹ Although the precise mechanism of action is not yet understood, the κ-receptor modulates the regulation of serotonin, including the activity of the presynaptic serotonin transporter (SERT).¹⁶³ SERT regulates the synaptic availability of serotonin (5-HT) by transporting released 5-HT back from the synaptic cleft into the neuron, and is the primary site of action for SSRIs.²²⁸ Preclinical trials have shown that activation of the κ-receptor may decrease SERT expression and activity, thereby decreasing 5-HT reuptake, in some regions where the κ-receptor is expressed.^231,232 κ-receptor agonists also increase dopamine transporter activity, but have no effect on noradrenergic transporter activity.²³³ However, most research on the κ-receptor system has been conducted in rodent models. Little evidence exists in support of increased serotonergic activity during treatment with buprenorphine, and the effects of buprenorphine on the monoamine system have not been investigated in people with dementia.^234-236

Even though buprenorphine has some anticholinergic effects, such as xerostomia and urinary retention, it is unlikely that combined anticholinergic effects have caused the observed interaction for two reasons: firstly, ACB score did not impact

discontinuation risk, and secondly, none of the participants who received buprenorphine used TCAs.

Frailty may also contribute to the increased risk of adverse events in those who used antidepressants and received buprenorphine, as frail individuals are characterised by impaired homeostasis and reduced resilience which increases their susceptibility to adverse drug effects and drug interactions.²³⁷ However, this does not explain why antidepressants were the only drug class to impact discontinuation risk.

As shown in Figure 6, the major difference in tolerability of buprenorphine TDS was not found between those who received buprenorphine versus placebo, but rather between those who used antidepressants and buprenorphine in combination versus those who did not. This suggests that buprenorphine TDS should be used with particular caution in people with dementia who also use antidepressants. New clinical trials with larger sample sizes are needed to fully elucidate the impact of concomitant drug use on risk of adverse events of buprenorphine TDS, and also to determine whether antidepressant use increases the risk of adverse events during treatment with other strong opioids in addition to buprenorphine TDS.

5.3.8 Challenges concerning research in people with dementia