TABLE 7

Preclinical examinations of medications with multiple mechanisms of action on the opioid withdrawal syndrome

Only results pertaining to effects of non-opioid drugs on opioid withdrawal symptoms are presented.

ReferenceDrugs Evaluated for Opioid Withdrawal Outcomes (Dose and Route)SpeciesSample SizeWithdrawal MethodDependence MethodWithdrawal Signs AssessedSummary of Withdrawal-Specific Results
Aceto and Bowman (1993)Buspirone (0.2, 0.4, and 0.8 mg/kg)Rhesus Monkey≥3Precipitated, naloxone (0.05 mg/kg, s.c.) 2 to 3 hours after last morphine administrationMorphine (3 mg/kg, s.c.) at minimum for ≥3 monthsAtaxia, body sag, fighting, jaw sag, lying down, ptosis, retching, restlessness, rigid abdominal muscles, slowing, vocalization, and wet dog shakesBuspirone dose dependently reduced rigid abdominal muscles, fighting, lying down, retching, restlessness, and vocalization and increased wet dog shakes.
Berthold et al. (1989)Clonidine (0.01, 0.03, 0.1, and 0.3 mg/kg), prazosin (0.1, 1, and 4 mg/kg), spiroperidol (0.05 and 0.5 mg/kg), 8-OH-DPAT (0.5, 1, 2, 4, 8 mg/kg); RU 24969 fumerate (0.125, 0.25, 0.5., 1, 2, and 4 mg/kg); Idazoxan; (−)-pindolol (1, 2, and 4 mglkg); (+)-SDZ 21-009 (1 mg/kg); (−)-SDZ 21-009 (1 mg/kg); buspironc (1, 2, 5, and 10 mg/kg); ipsapirone (1, 3, and 10 mg/kg); yohimbine (0.5 and 2 mg/kg); flesinoxan (0.5, 1, and 3 mg/kg); Rauwolscine (0.5 and 2 mg/kg), WY 26392 (0.5, 2 mg/kg), haloperidol (0.1, 0.5, and 1.0 mg/kg); pCPA (150 mg/kg). Administered subcutaneously.Mouse10Precipitated, naloxone (1 mg/kg, i.p.) on day 5Morphine (75 mg) subcutaneous implant for 5 daysJumping8-OH-DPAT (1 mg/kg), RU 24969 (0.25–4 mg/kg), buspirone (2 mg/kg) (5-HT1 agonists), ipsapirone (10 mg/kg), and flesinoxan (all doses) (5-HT1 agonists) decreased jumping. Idazoxan (all doses), prazosin (1 and 4 mg/kg), rauwolscine (2 mg/kg), WY 26392 (all doses), and yohimbine (all doses) (α-adrenoreceptor antagonists) also decreased jumping. Spiroperidol (5-HT1 antagonist) pretreatment had no effect alone but increased jumping from 8-OH-DPAT and buspirone; no effect of spiroperidol pretreatment on RU24969 and idazoxan. Haloperidol pretreatment enhanced 8-OH-DAPAT–related jumping. Pretreatment (−)-pindolol and (−)-SDZ 21-009 (β-adrenoreceptor/5-HT1A and 5-HT1B antagonists) decreased ability of RU 24969 to suppress jumping. (+)-SDZ21-009 did not impact RU 24969. 8-OH-DAPAT unaffected by (−)-pindolol. pCPA, clonidine (α2 agonist), and (−)-pindolol had no effects.
Cappendijk et al. (1994)β-Carboline (20 mg/kg), Ibogaine (40 mg/kg). Administered intraperitoneally.Rat10Precipitated, naloxone (4 mg/kg, i.p.) on day 3Morphine (75 mg) subcutaneous implant for 3 daysChewing, diarrhea, grooming, jumping, penile licking, ptosis, rearing, rhinorrhea, teeth- chattering, wet dog shakes, vocalization on touch, and total withdrawal scoreβ-Carboline (20 mg/kg) decreased the total withdrawal score, chewing, diarrhea, grooming penile licking, rearing, and teeth chattering. Ibogaine decreased the total withdrawal score, chewing, diarrhea, penile licking, and teeth chattering.
Dzoljic et al. (1988)Ibogaine (4, 8, and 16 μg). Administered intracerebroventricularly.Rat10Precipitated, naloxone (5 mg/kg, i.p.) on day 3Morphine (85 mg) subcutaneous implant for 3 daysChewing, diarrhea, digging, ejaculation, grooming, head holding, head shakes, jumping, paw tremor, penile licking, ptosis, rearing, rhinorrhea, salivation, scratching, stretching, teeth chattering, urination, vocalization on touch, wet dog shakes, and writhingIbogaine significantly reduced jumping and salivation (8 and 16 μg), chewing, digging, head hiding, penile licking, rearing, teeth chattering, and writhing (all doses), relative to cerebrospinal fluid control condition.
Francés et al. (1992)Ibogaine (30 mg/kg). Administered intraperitoneally.Mouse5–32Precipitated, naloxone (5 mg/kg, i.p.) on day 1, 2, 3, 4, or 5 (varied based on group)Escalating morphine doses up to 100 mg/kg, i.p., for up to 5 days (varied based on group)Body shakes, body weight, dropping, diarrhea, and jumpingIbogaine (30 mg/kg) increased jumping and did not decrease any withdrawal signs.
Glick et al. (1992)Ibogaine (20, 40, and 80 mg/kg). Administered intraperitoneally.Rat7–17Precipitated, naltrexone (1 mg/kg, i.p.) on day 6Morphine (50 mg) subcutaneous implant for 5 daysBurying, diarrhea, grooming, paw shaking, teeth chattering, and wet dog shakesIbogaine decreased diarrhea, teeth chattering, and wet dog shakes (40, 80 mg/kg), and grooming (all doses).
Hine et al. (1975a)Cannabidiol (10 mg, kg). Administered intraperitoneallyRat7Precipitated, naloxone (4 mg/kg, i.p.) on day 3Morphine (75 mg) subcutaneous implant for 3 daysAbnormal posture, chewing, defecation, diarrhea, ear blanching, ptosis, teeth chattering, vocalization, wet dog shakes, and total withdrawal scoreCannabidiol (10 mg/kg) had no effect.
Hine et al. (1975c)THC (2 mg/kg), cannabidiol (10 mg/kg), THC (2 mg/kg) + Cannabidiol (10 mg/kg). Administered intraperitoneally.Rat8 to 9Precipitated, naloxone (4 mg/kg, i.p.) on day 3Morphine (75 mg) subcutaneous implant for 3 daysAbnormal posture, audible grinding, chewing, defecation, escapes, diarrhea, ear blanching, ptosis, teeth chattering, vocalization on touch, wet dog shakes, and writhingTHC (2 mg/kg) decreased total withdrawal scores and defecation, and diarrhea. Cannabidiol alone had no effect. THC (2 mg/kg) + Cannabidiol (10 mg/kg) decreased total withdrawal scores, defecation, ear blanching, escapes, and wet dog shakes.
Kang et al. (2008)Mirtazapine (3, 10, and 30 mg/kg). Administered intraperitoneally.Rat40Precipitated, naloxone (1 mg/kg, i.p.) on day 10Morphine 10 mg, s.c., twice a day for 10 daysBody weight, chewing, digging, escape attendance, grooming, rearing, scratching, teeth chattering, and wet dog shakesMirtazapine reduced chewing (10 and 30 mg/kg), and escape attendance, grooming, and teeth chattering (all doses). Mirtazepine (10 and 30 mg/kg) reduced total withdrawal score.
Koyuncuoğlu et al. (1990)Ketamine (0.5 and 1 mg/kg, i.v.), dextromethorphan (1 and 2 mg/kg, i.p.).Rat10–16Precipitated, naloxone (2 mg/kg, i.p.) on day 3Morphine (225 mg) subcutaneous implant + F16 for 3 daysDefecation, diarrhea, flying jumping, ptosis, teeth chattering, wet dog shakes, and writhingKetamine (1 mg/kg) decreased defecation, jumping, and teeth chattering, but increased wet dog shakes. Dextromethorphan (1 mg/kg) decreased flying and teeth chattering, and (2 mg/kg) decreased all signs except writhing.
Leal et al. (2003)Ibogaine (40 and 80 mg/kg), MK-801 (0.15 and 0.3 mg/kg), ibogaine (40 mg/kg) + MK-801 (0.15 mg/kg). Administered intraperitoneally.Mouse10–13Precipitated, naloxone (5 mg/kg, i.p.) on day 4Escalating morphine doses up to 225 mg/kg, i.p., by day 3JumpingAll doses of ibogaine and MK-801 (NMDA antagonist) decreased jumping. Ibogaine (40 mg/kg) and MK-801 (0.15 mg/kg) coadministration decreased jumping at the level observed for the high dose of each drug independently.
Lu et al. (2001)Venlafaxine (10 and 20 mg/kg). Administered intraperitoneally.Rat12Precipitated, naloxone (2 mg/kg, i.p.) on day 5Escalating morphine doses up to 40 mg/kg, s.c., by day 5Body weight, diarrhea, exploring, irritability, jumping, lacrimation, piloerection, ptosis, teeth chattering, wet dog shakes, and writhingVenlafaxine (10 and 20 mg/kg) decreased diarrhea, exploring, jumping, piloerection, and shakes. Venlafaxine (20 mg/kg per kilogram) also decreased irritability, lacrimation, wet dog shakes, and writhing.
Mash et al. (2016)Noribogaine (10, 30, 56, and 100 mg/kg). Intragastric administrationMouse5–11Precipitated, naloxone (3 mg/kg, i.p.) on day 4Escalating morphine doses up to 75 mg/kg, s.c., for 4 daysBody tremors, diarrhea, jumping, and paw tremorsNoribogaine decreased body tremors (30 and 100 mg/kg), paw tremors (100 mg/kg), and jumping (30, 56, and 100 mg/kg).
Panchal et al. (2005)18-MC (5, 10, and 25 μg/1 μl). Infused into intramedial habenula, locus coeruleus, or interpeduncular nucleus.Rat5–10Precipitated, naltrexone (1 mg/kg, i.p.) on day 8 (immediately following intracerebral drug infusion)Escalating morphine doses up to 80 mg/kg, s.c., 7 daysBurying, diarrhea, grooming, rearing, teeth chattering, and wet dog shakesIntramedial habenula 18-MC decreased body weight loss (10 μg) and burying (10 μg). Teeth chattering decreased at 5 μg and increased at 10 μg. Intralocus coeruleus 18-MC dose decreased diarrhea (10 μg), burying (all doses), teeth chattering (5 and 20 μg), and wet dog shakes (10 μg). Intrainterpeduncular nucleus 18-MC decreased burying (5 μg) and rearing (10 μg) and increased diarrhea (5 μg) and teeth chattering (20 μg).
Parker and Siegel (2001)Ibogaine (40 mg/kg). Administered intraperitoneally.Rat28 total (individual group size NR)Precipitated, naloxone (1 mg/kg, s.c.) on day 3Morphine (20 mg/ml) subcutaneous implant for 2 daysMouth movements, penile licking, rearing, teeth chattering, and wet dog shakesIbogaine (40 mg/kg) decreased mouth movements, penile licking, and teeth chattering.
Rho and Glick (1998)18-MC (10, 20, or 40 mg/kg). Administered intraperitoneally.Rat6–8Precipitated, naltrexone (1 mg/kg, i.p.) on day 8Escalating morphine up to 140 mg/kg, s.c., for 7 daysBody weight, burying, diarrhea, flinching, grooming, teeth chattering, and wet dog shakes18-MC decreased body weight loss (40 mg/kg), burying (20 and 40 mg/kg), diarrhea (40 mg/kg), teeth chattering (20 and 40 mg/kg), and wet dog shakes (20 mg/kg).
Schreiber et al. (2003)Mianserin (25 mg/kg), trazodone (50 mg/kg), mianserin (25 mg/kg) + trazodone (50 mg/kg). Administered subcutaneously.Mouse>10Precipitated, naloxone (1 mg/kg, s.c.)High morphine group: escalating morphine up to 160 mg/kg, s.c., by day 8; low morphine: escalating morphine up to 40 mg/kg, s.c., by day 8Grooming, jumping, and rearingMianserin (25 mg/kg), trazodone (50 mg/kg), and mainserin (25 mg/kg) + trazodone (50 mg/kg) combination reduced jumping, rearing, and grooming in both high and low morphine groups.
Sharpe and Jaffe (1990)Ibogaine (5, 10, 20, and 40 mg/kg). Administered subcutaneously.Rat6Precipitated, naloxone (0.5 mg/kg, s.c.) on day 3Morphine (75 mg) subcutaneous implant for 3 daysActivity, grooming, lacrimation, mouth movement, paw shakes, penile licking, rhinorrhea, salivation, stretching, teeth chattering, wet dog shakes, and total withdrawal scoreIbogaine decreased grooming (10 mg/kg) and increased teeth chattering (5 mg/kg).
Streel et al. (2005)Ketamine (2.5 mg/kg), Midazolam (0.25 mg/kg). Administered intramuscularlyRat10Precipitated, naloxone (1 mg/kg, s.c.) on day 3, administered three times (total daily dose 3 mg/kg, s.c.)Escalating morphine up to 150 mg/kg, s.c., for 3 daysAbnormal posture, cheek tremors, defecation, escape attempts, head lift, jumping, mastication, salivation, sniffing, teeth chattering, urination, vocalization on touch, wet dog shakes, and total withdrawal scoreKetamine (2.5 mg/kg) decreased defecation, urination, and total withdrawal scores. Midazolam (0.25 mg/kg) decreased urination and total withdrawal scores.
  • pCPA, para-chlorophenylalanine; 18-MC, 18-methoxyroconaridine; NR, not reported.