A novel therapeutic for opioid use disorder targeting the cholinergic system

Commentary

The United States is currently in the grips of an opioid epidemic, which according to recent data from the National Institute on Drug Abuse (NIDA) claimed 47,000 American lives in 2017. The addictive behavior at the heart of the epidemic is fueled by the compulsive pursuit of drug reinforcement and preoccupation with the cues that predict it¹. Although opioid maintenance medications, such as methadone, buprenorphine, and naltrexone, have been shown to reduce opioid overdoses, these medications are plagued by low rates of retention, as well as by adverse cognitive, physical, and emotional side effects². The limitations of opioid maintenance medications, in conjunction with the urgency of the opioid epidemic, highlight the immediate and unmet need for coadjuvant treatment strategies, which not only can reduce or eliminate opioid use but also can treat the drug-related attentional biases and other quality-of-life disturbances that accompany the addiction. Against this backdrop, the cholinergic system was recently posited as an exciting new therapeutic target for treating individuals with opioid use disorder (OUD)².

In this issue of The American Journal on Addictions, Carroll et al.³ provide seminal clinical evidence supporting this suggestion, by showing that a cholinergic medication, galantamine, may have efficacy in improving opioid-related outcomes in OUD. Galantamine is a cognitive enhancer principally used in the treatment of mild to moderate Alzheimer’s disease and similar neuropsychiatric disorders characterized by cognitive decline. Its mechanism of action is to increase synaptic acetylcholine (ACh) levels, primarily by inhibiting activity of acetylcholinesterase, which is the enzyme that catalyzes the breakdown of ACh. However, unlike more selective cholinesterase inhibitors such as donepezil, galantamine is thought to have a dual mechanism of action, additionally acting as a positive allosteric modulator of nicotinic receptors.

In their manuscript, Carroll et al.³ reported the results of a galantamine clinical trial among methadone-maintained individuals who were also cocaine dependent. As part of the trial, participants received, in a double-blind fashion, galantamine or placebo over a 12-week trial that also included a 6-month follow-up, with a highly impressive 97% retention rate. The trial was originally conceived for testing reductions in cocaine use, but in the current study the authors performed a secondary analysis to examine effects of galantamine on opioid use. Results showed that, compared with placebo, galantamine treatment produced fewer opioid-positive urines throughout the study (corroborated with self-reported abstinence), a positive therapeutic effect that extended into the 6-month follow-up period; time to first opioid use was also significantly delayed (i.e., by more than a month) in the galantamine group compared with the placebo group. Importantly, a positive therapeutic effect of galantamine was detected even among participants who had used opioids during the baseline period, prior to randomization, as indicated by a main effect of the galantamine treatment but no interaction with baseline opioid use. This finding is noteworthy because participants who entered treatment urine-positive for opioids submitted more opioid-positive urines throughout the study, consistent with prior reports in stimulant use disorder showing that individuals who enter treatment urine-positive for drugs of abuse generally have poorer outcomes⁴.

Interestingly, the authors hypothesized that galantamine would reduce opioid use via improvements in attention and memory, which are core cognitive functions of the brain cholinergic system⁵. Impairments in these cognitive domains have been consistently shown in individuals with OUD⁶, and are likely to produce downstream effects on goal-directed behavior and psychosocial functioning, which in turn are needed to resist drug-related temptations and sustain the flexibility and motivation for long-term abstinence⁷; for these reasons, intact cognition is a known predictor of treatment engagement and eventual success in OUD and other addictions⁸. Thus, the hypothesis of improvement via attentional or memory mechanisms was scientifically sound, and to their credit, the authors examined these processes as potential mediators of the clinical improvement. Contrary to expectations, however, galantamine had no discernible effects on cognition, suggesting that the therapeutic signal cannot be explained by simple cognitive remediation. This null finding does not diminish the importance of the primary trial results, but does indicate that the behavioral mechanism remains to be determined.

One possibility, which the authors briefly mention in their Discussion, is that galantamine’s therapeutic signal may have been driven by restorative effects on reward processing, another important function of the brain cholinergic system, often in interaction with dopamine. The pedunculopontine tegmental nucleus (PPTg), one of several cholinergic midbrain nuclei, projects to the ventral tegmental area (VTA) with the apparent function of performing a gating role, signaling to the VTA whether stimuli encountered in the environment are salient for reward or require motor responses⁹. In addition, cholinergic interneurons in the striatum contribute to reward processing and the reinforcement of reward-related behaviors¹⁰. Accordingly, ACh transmission appears to play a critical role in cue-induced opioid-seeking behavior¹¹, and is closely linked to opioids acquiring heightened motivational properties¹². An integration of these perspectives suggests that the brain cholinergic system contributes to the attentional and reward processing functions that subserve approach behavior toward opioid cues and eventual drug use; galantamine, then, could be acting to modulate a cholinergically-mediated attentional bias toward opioid-related cues culminating in reduced drug use. As the authors did not measure drug-related attentional biases, it will be very interesting to evaluate this and related hypotheses in future studies.

More specifically, future studies should include measures of drug-biased attention and drug-biased decision-making as potential mediators of galantamine-induced reductions in drug use. Attentional bias may be measured with behavioral tasks, as well as during functional neuroimaging to characterize the underlying circuitry and the perturbations associated with the bias. Prior studies have suggested that the inclusion of a drug-related context into a standard neuropsychological test may aid in detecting subtle cognitive deficits in addicted individuals^13,14. Another interesting direction for future research is to uncover the molecular mechanisms of galantamine’s therapeutic effects in OUD – either alone or in combination with measures of drug-biased attention for a comprehensive, multimodal study of target engagement. Positron emission tomography (PET) radiotracers labeling various cholinergic targets can be employed for this purpose. These could include nicotinic receptor targets (e.g., through the use of well-characterized tracers such 2-FA¹⁵), or could include presynaptic targets such as the vesicular cholinergic transporter (e.g., through the use of the new tracer [¹⁸F]VAT).

Taken together, Carroll et al.³ appear to have uncovered a novel and potentially impactful therapeutic for OUD, a disease that is devastating the United States. While the behavioral mechanism remains elusive, this report nonetheless suggests numerous exciting directions for future research. Future investigations have the potential to yield valuable information on galantamine as a medication to push forward clinical practice, as well as yield valuable scientific knowledge on the brain cholinergic system and its involvement in OUD and other addictions. If the Carroll et al.³ results are replicated and extended in future trials and clinical laboratory studies, and given that galantamine has shown efficacy in other addictions such as alcohol and cigarette smoking (as the authors review in their manuscript), it is possible that galantamine may emerge as an exciting, next-generation adjunctive medication for improving clinical outcomes in OUD.