TABLE 2.
Therapeutic effects and side effects of KOR agonists in clinical studies.
| KOR agonist | Clinical therapeutic effects | Side effects | References |
|---|---|---|---|
| ADL 10-0101 | Phase I: completed: safety assessment in healthy volunteers (Adolor Corporation) (10 μg/kg/min, i.v. s.e all) [1] | ↑Headache, restlessness n/e BP, HR, respiratory rate, nausea (10 μg/kg/min, i.v.) [1] | Eisenach et al. (2003) [1] |
| Phase II: Effectiveness in reducing pain in patients suffering from chronic pancreatitis (10 μg/kg/min, i.v.) n = 6; s.e., all; age 18–60 years [1] | |||
| Asimadoline | Phase II: completed (12/2007). Safety and efficacy of asimadoline (0.15, 0.5, 1.0 mg, p.o.) in the treatment of patients with IBS n = 596; s.e., all; age 18–79 years [NCT00454688]. | ND | |
| Phase II: completed (3/2007). Effect of Asimadoline (0.5–1 mg, p.o) on acute pain attacks (IBS) n = 100; s.e., all; age 18–65 years [NCT00955994]. | |||
| Phase II: completed (6/2017). Safety, tolerability, and efficacy of asimadoline (5 mg, p.o.) in patients with pruritus associated with atopic dermatitis n = 249; s.e., all; age 18 years and above [NCT02475447]. | |||
| Phase III: completed (6/2013). Safety and efficacy of asimadoline (0.5 mg, p.o.) in treating Diarrhea-Predominant IBD n = 611; s.e., all; age 18–79 years [NCT01100684]. | |||
| Phase II: terminated for post-operative ileus n = 35; s.e., all; age 18–80 years (poor enrolment) [NCT00443040]. | |||
| Enadoline | Pilot Study: Characterisation; pharmacodynamic effects (10–80 80 µg/70 kg, i.m.) n = 9; s.e., all; age 22–47 years | Psychotomimetic effects, skin prickling, unsteady gait (160-µg/70 kg, i.m.) [2] | Walsh et al. (2001) [2] |
| Fedotozine | Phase II: completed (1994): | No pattern of drug related adverse effects [3] | Fraitag et al. (1994) [3]; Read et al. (1997) [4]; Barber and Gottschlich (1997) [5]; Delvaux (2001) [6] |
| ↓ Post-prandial fullness, bloating, nausea | |||
| ↓ Abdominal pain (30 and 70 mg, p.o.) n = 146; s.e., all; age 43–55 years [3] | |||
| Phase III: completed (1997): effective for the relief of functional dyspepsia (30 mg thrice daily, p.o.) n = 333; s.e., all [4] | |||
| Phase III: terminated: IBS and dyspepsia; terminated (lack of efficacy) [5, 6] | |||
| Niravoline | Phase II: completed: Effective treatment of patients with cirrhosis and water retention (0.1–2 mg, i.v.) n = 18; s.e., all; age 52± years [7] | ↑ Diuresis (0.1–2 mg, i.v.) | Gadano et al. (2000) [7] |
| ↑ Aquaretic effect (0.5 and 1 mg, i.v.) [7] | |||
| Spiradoline (U62,066) | Phase I: completed (12/2009): Bipolar Depression: n = 24; s.e., male; age 21–55 years [NCT00988949]. | ↑ Diuresis (1.6 and 4.0 μg/kg, i.m.) | Peters et al. (1987) [8]; Chappell et al. (1993) [9]; Ur et al. (1997) [10] |
| Phase I: Diuretic actions (2–6 μg/kg, i.m.)[8] | ↑ Prolactin, growth hormone and cortisol levels (1.6 and 4.0 μg/kg, i.m.) [10] | ||
| Clinical study: Effect of Spiradoline on Tourette’s syndrome. | |||
| ↓ Frequency of tics, Low doses (0.8 μg/kg, i.m) higher doses either worsened tics, or had n.e. n = 10; s.e., male; age 20–47 years [9] | |||
| Noribogaine (O-desmethylibogaine/12-hydroxyibogamine) | Phase I: completed (2014): Safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine (3–60 mg/kg, p.o.) n = 36; s.e., male; age 18–55 years [ACTRN12612000821897] [11] | Headache (3 mg), Epistaxis (placebo) [11] | Glue et al. (2015) [11] |
| Phase I and II: recruiting patients (Exp. completion date: 9/2023) Efficacy, safety and tolerability of Ibogaine for opioid withdrawal patients (3–12 mg/kg, p.o.) n = 110; s.e., all; age 18–55 years [NCT05029401] | |||
| Nalfurafine | Clinically approved (Japan) (2009) Remitch for medication-resistant pruritus in patients with hemodialysis [12] | Insomnia (≥3% (5 μg/kg, p.o.) [13] | Inan et al. (2009) [12]; Kumagai et al. (2010) [13] |
| Phase III: completed (9/2009): For the treatment of pruritus in patients receiving hemodialysis (5 μg, p.o.) n = 104; s.e., all; age 20 years and older [NCT01513161]. | |||
| Phase II: completed (3/2018): Nalfurafine as a treatment for pruritus in patients with primary biliary cholangitis n = 44; s.e., all; age 18 years and older [NCT02659696]. | |||
| Phase II: completed (12/2009): Pruritus in patients with chronic liver disease (2.5–10 μg, p.o.) n = 120; s.e., all; age 20 years and older [NCT00638495]. | |||
| Phase III: recruiting patients (Exp. completion date 10/2021): Efficacy, safety and plasma concentration of nalfurafine for treatment of refractory pruritus (5 μg, p.o.) n = 133; s.e., all; age 18 years and older [NCT04728984]. | |||
| CR665 | Phase II: completed (2009): | No serious side effects Paresthaesia, dizziness, somnolence and increased prolactin levels [14] | Arendt-Nielsen et al. (2009) [14] |
| ↓ Visceral pain in a human model of oesophageal distension (0.36 mg/kg; i.v.) n = 18; s.e., male; age 19–43 years [14] | |||
| Difelikefalin (CR845) | FDA approved (8/2021): (Dose: 0.5 μg/kg, 3x weekly, i.v.) n = 222; s.e., all; age 18–25 years [NCT03998163] [15] | Common adverse reactions: diarrhoea, dizziness, nausea, gait, hyperkalaemia. headache 0.5 μg/kg 3x weekly, i.v.) occurring in ≥ 2% of recipients (n = 424) [16] | Wang et al. (2021) [15]; Deeks (2021) [16] |
| Phase II: completed (1/2016): osteoarthritis of the hip or the knee (0.25–5 mg, p.o.) n = 81; s.e., all; age 25 and above [NCT02524197] | |||
| Phase II: completed (4/2021): Pruritus (atopic dermatitis) (0.25–1 mg, p.o.) n = 401; s.e., all; age 18–80 years [NCT04018027] | |||
| Phase II: recruiting patients (Est. completion date, 3/2022): Pruritus (notalgia paraesthetica) (2 mg, p.o.) n = 120; s.e., all; age 18–80 years [NCT04706975] | |||
| Phase II: recruiting patients (Est. completion date, 6/2022): Pruritus (primary biliary cholangitis) (1 mg, p.o.) n = 60; s.e., all; age 18–80 years [NCT03995212] | |||
| Apadoline | Phase I: Reduced pain (0.1, 0.5, and 1.0 mg, p.o.) n = 20; s.e., male [17] | Mild drowsiness and headache (1 mg, p.o.) [17] | Lötsch et al. (1997) [17] |
| Salvinorin A | Drug Effect: Phase I and II: completed (3/2020). Effects on human brain activity and connectivity, n = 13; age 21–50 years; s.e., all [NCT03418714] | ↑ Psychoactive effects inh. (0.25 mg, inh.) | Maqueda et al. (2015) [18]; Addy (2012) [19]; MacLean et al. (2013) [20] |
| Phase I: completed (11/2013): Hallucinogenic effects n = 14; age 21–65 years; s.e., all [NCT00996411]. | ↑ Synesthesia (inh.0.25 mg) [18] | ||
| Phase I: ongoing (Est. completion date: 12/2021): Psychotomimetic Effects in healthy people n = 66; age 18–45 years; s.e., all [NCT00700596]. | ↑ Hallucinations (inh.100 µg) [19] | ||
| Phase I: completed (2019): For effects on mood and performance completed n = 20; age 21–50 years; s.e., all [NCT02033707]. | ↑ Dissociative effects (inh. 0.375–21 μg/kg) [20] |
Abbreviations: BP, blood pressure; HR, heart rate; i.m., intramuscular; i.v., intravenous; inh, inhalation; ND, not determined; n.e., no effect; n, number of participants; p.o., per oral; s.c., subcutaneous; s.e., sexes eligible for study.