Table 1.
Clinical trials that KOR partial agonism or antagonism improves substance use disorder (pain is noted). Nalmefene (Selincro®), a mu opioid receptor inverse agonist with weak partial KOR agonist properties, is used in the treatment of alcohol use disorder. Buprenorphine (partial mu opioid agonist, ORL-1 agonist, KOR antagonist/partial KOR agonist, and delta opioid antagonist) and naloxone (Zubsolv®, Suboxone®) combination has been used for treating opioid use disorder (Heo and Scott 2018) and this combination was reported to reduce pain. Buprenorphine in combination with samidorphan (MOR antagonist) showed beneficial effects over placebo to reduce symptoms in major depressive disorder patients who had inadequate responses to antidepressants, although this drug combination was recently rejected by the US Food and Drug Administration. Polymorphisms in the KOR gene are associated with opioid dependence. Previous reviews have discussed the safety and efficacy of buprenorphine for the treatment for chronic pain (Davis et al. 2018; Pergolizzi and Raffa 2019) or opioid use disorder (Parida et al. 2019)
| Species | Sex | Protocol | KOR ligand | Brain region | Model | Outcome | Ref |
|---|---|---|---|---|---|---|---|
| Human | M/F | Phase IV clinical trial | Nalmefene | na | EtOH-dependent outpatients | ↓ Heavy drinking days ↓ Total EtOH consumption |
(Barrio et al. 2018) |
| Human | M/F | Double -blind Multicenter Randomized | Nalmefene | na | AUD (>60 g/day M >40 g/day F) | ↓ Heavy drinking days ↓ Total EtOH consumption |
(Miyata et al. 2019) |
| Human | M/F | FMRI Placebo controlled, double-blind | Nalmefene | Putamen, angular gyrus, supramarginal gyrus, (↔amygdala) | AUD | ↑ BOLD to emotional faces in areas responsible for empathy and social cognition, attentional shift happy > fearful | (Vollstädt-Klein et al. 2019) |
| Human | M/F | Double-blind, placebo control trial | Nalmefene | na | AUD | ↓ Heavy drinking days | (Mason et al. 1999) |
| Human | Male | FMRI with i.v. EtOH (6% v/v to achieve 80 mg/dL) | Nalmefene | Striatum | Heavy drinkers | ↓ BOLD during reward anticipation | (Quelch et al. 2017) |
| Human | ORPK1 gene polymorphism (rsl0958350-rs7016778-rsl2675595) | na | Methadone maintenance for OUD | Polymorphism was associated with opioid withdrawal | (Wang et al. 2014) | ||
| Human | ORPK1 gene polymorphism (rs997917, rs6985606) | na | Methadone maintenance for OUD | Polymorphism was associated with opioid dependence | (Albonaim et al. 2017) | ||
| Human | ORPK1 gene polymorphism (KOR 36G > T SNP, rs6473797, rsl6918842, rs3802279) | na | Heroin-dependence | Polymorphism was associated with heroin dependence | (Yuferov et al. 2004; Gerra et al. 2007; Levran et al. 2008; Yuanyuan et al. 2018) | ||
| Human | Male | Suicide ideation for inpatients | Buprenorphine (sublingual) | na | OUD and major depressive disorder | ↓ Suicide ideation | (Ahmadi et al. 2018) |
| Human | M/F | Multicenter double-blind placebo controlled trial | Buprenorphine/samidorphan (not approved by FDA) | na | Major depressive disorder | ↓ Depression (HAM-D, 17-item scale, Montgomery-Åsberg depression rating scale and the clinical global impressions severity scale) | (Ehrich et al. 2015a; Fava et al. 2016) |
| Human | M/F | OUD | Buprenorphine-naloxone | na | OUD | ↓ Pain intensity (in non-chronic pain cohorts) | (Becker et al. 2015) |
| Human | M/F | In patient oxycodone selfadministration | Buprenorphine-naloxone | na | OUD/chronic pain transitioning from opioid to Bup/Nx | ↓ Pain ratings when switched to Bup/Nx ↔ between placebo and oxycodone preference, those that showed oxycodone preference had lower Bup/Nx dose, more withdrawal and more pain | (Roux et al. 2013) |
| Human | M/F | Pilot clinical trial | Buprenorphine-naloxone | na | OUD/chronic pain transitioning from opioid to Bup/Nx | ↓ Average and worse pain after switching to Bup/Nx | (Rosenblum et al. 2012) |
| Human | M/F | Postsecondary analysis of randomized trials | Buprenorphine-naloxone | na | OUD | >50% reported pain at baseline Improvement in pain correlated with increased retention of treatment | (Shulman et al. 2020) |
| Human | M/F | Open-label randomized | Buprenorphine-naloxone | na | OUD | ↔Pain intensity, affective pain or sensory pain but women had greater affective pain than men | (Latif et al. 2019) |
| Human | M/F | Postsecondary analysis of randomized trials | Buprenorphine-naloxone | na | OUD | Patients with flare-up pain were at higher risk of relapse | (Griffin et al. 2016) |
| Human | M/F | Postsecondary analysis of randomized trial | Buprenorphine-naloxone | na | OUD with chronic pain | ↓ Pain over course of 12 week treatment, those with high pail volatility were more likely to relapse | (Worley et al. 2015, 2017) |
| Human | Male | Case study (40 year+ with chronic pain) | Buprenorphine-naloxone | na | Chronic pain with long-term opioid use | ↓ Pain, improved function and quality of life | |
| Human | Male | Randomized trial | Buprenorphine-naloxone vs. methadone | na | Chronic pain and OUD | ↓ Pain at 6 months | (Neumann et al. 2013) |