A double-blind, double-dummy, randomized controlled study of memantine versus buprenorphine in naloxone-precipitated acute withdrawal in heroin addicts


  • Kushal Jain, MD
  • Raka Jain, PhD, FRSC Chem
  • Anju Dhawan, MD




memantine, buprenorphine, heroin, opioids, opioid withdrawal


Objectives: To compare the efficacy of memantine with buprenorphine in the suppression of naloxone-precipitated acute withdrawal in heroin-dependent male subjects in an inpatient setting.
Setting: Inpatient unit of tertiary level deaddiction facility.
Participants: Forty-five treatment-seeking heroin-dependent males.
Interventions: Subjects stabilized on 650 mg of dextropropoxyphene for 5 days were randomly divided into two groups on the sixth day: group A (n = 25) received 20 mg of memantine with buprenorphine placebo, and group B (n = 20) received 2 mg of buprenorphine with memantine placebo. Acute withdrawals were precipitated with naloxone (0.4 mg, intravenously) and were assessed using subjective and objective opioid withdrawal scales (SOWS and OOWS) and two separate visual analogue scales (VASs) for pain and dysphoria at baseline prior to test drug administration and again after the precipitation of acute withdrawal.
Main outcome measures: Severity of precipitated opioid withdrawals.
Results: Baseline opioid withdrawal symptoms in both groups did not differ significantly. After the precipitation of acute withdrawal, there were no significant differences between subjects in both groups on OOWS and both VASs but showed significant difference on SOWS. When changes in ratings from baseline (and after naloxone-precipitated acute withdrawal) were compared between the two groups, a significant difference in the change in SOWS scores was observed with greater decrease in withdrawal scores in the buprenorphine group.
Conclusions: Memantine has comparable efficacy to buprenorphine in the suppression of objective signs of naloxone-precipitated acute opioid withdrawal; however, its role in the suppression of subjective symptoms is debatable.

Author Biographies

Kushal Jain, MD

Masters Program in Public Health (Student), Faculty of Medicine, Lund University, Sweden; Formerly at Department of Psychiatry, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India. E-mail: drkushal80@gmail.com

Raka Jain, PhD, FRSC Chem

Professor, Department of Psychiatry, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India.

Anju Dhawan, MD

Associate Professor, National Drug Dependence Treatment Centre, All India Institute of Medical Sciences, New Delhi, India.


O’Brien CP: Drug addiction and drug abuse. In Goodman LS, Gilman A (eds.): The Pharmacological Basis of Therapeutics. New York: Macmillan Publication, 1996: 557-577.

Popik P, Skolnick P: The NMDA antagonist memantine blocks the expression and maintenance of morphine dependence. Pharmacol Biochem Behav. 1996; 53(4): 791-797.

Popik P, Danysz W: Inhibition of reinforcing effects of morphine and motivational aspects of naloxone precipitated opioid withdrawal by N-methyl-D-aspartate receptor antagonist, memantine. J Pharmacol Exp Ther. 1997; 280(2): 854-865.

Medvedev IO, Dravolina OA, Bespalov AY: Effects of N-methyl-D-aspartate receptor antagonists on discriminative stimulus effects of naloxone in morphine-dependent rats using the Y-maze drug discrimination paradigm. J Pharmacol Exp Ther. 1998; 286(3): 1260-1268.

Sukhotina IA, Bespalov AY: Effects of the NMDA receptor channel blockers memantine and MRZ 2/579 on morphine withdrawal-facilitated aggression in mice. Psychopharmacology (Berl). 2000; 149(4): 345-350.

Zhu H, Jenab S, Jones KL, et al.: The clinically available NMDA receptor antagonist dextromethorphan attenuates acute morphine withdrawal in the neonatal rat. Brain Res Dev Brain Res. 2003; 142(2): 209-213.

Mendez IA, Trujillo KA: NMDA receptor antagonists inhibit opiate antinociceptive tolerance and locomotor sensitization in rats. Psychopharmacology (Berl). 2008; 196(3): 497-509.

Harris AC, Rothwell PE, Gewirtz JC: Effects of the NMDA receptor antagonist memantine on the expression and development of acute opiate dependence as assessed by withdrawalpotentiated startle and hyperalgesia. Psychopharmacology (Berl). 2008; 196(4): 649-660.

Koyuncuoglu H, Saydam B: The treatment of heroin addicts with dextromethorphan: A double-blind comparison of dextromethorphan with chlorpromazine. Int J Clin Pharmacol Ther Toxicol. 1990; 28(4): 147-152.

Koyuncuoglu H: The treatment with dextromethorphan of heroin addicts. In Loimer N, Schmid R, Springer A (eds.): Drug Addiction and AIDS. Vienna, Austria: Springer, 1991: 320-329.

Koyuncuoglu H: The combination of tizanidine markedly improves the treatment with dextromethorphan of heroin addicted outpatients. Int J Clin Pharmacol Ther. 1995; 33(1): 13-19.

Bisaga A, Gianelli P, Popik P: Opiate withdrawal with dextromethorphan. Am J Psychiatry. 1997; 154(4): 584.

Rosen MI, McMahon TJ, Woods SW, et al.: A pilot study of dextromethorphan in naloxone-precipitated opiate withdrawal. Eur J Pharmacol. 1996; 307(3): 251-257.

Bisaga A, Comer SD, Ward AS, et al.: The NMDA antagonist memantine attenuates the expression of opioid physical dependence in humans. Psychopharmacology (Berl). 2001; 157(1): 1-10.

McShane R, Areosa Sastre A, Minakaran N: Memantine for dementia. Cochrane Database Syst Rev. 2006; (2): CD003154.

Möbius HJ: Memantine: Update on the current evidence. Int J Geriatr Psychiatry. 2003; 18 (Suppl 1): S47-S54.

Kornhuber J, Weller M, Schoppmeyer K, et al.: Amantadine and memantine are NMDA receptor antagonists with neuroprotective properties. J Neural Transm Suppl. 1994; 43: 91-104.

Kornhuber J, Quack G: Cerebrospinal fluid and serum concentrations of the N-methyl-D-aspartate (NMDA) receptor antagonist memantine in man. Neurosci Lett. 1995; 195(2): 137-139.

Lipton SA: Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond. Nat Rev Drug Discov. 2006; 5(2): 160-170.

Parsons CG, Danysz W, Quack G: Memantine and the amino-alkyl-cyclohexane MRZ 2/579 are moderate affinity uncompetitive NMDA receptor antagonists–In vitro characterisation. Amino Acids. 2000; 19(1): 157-166.

Krupitsky EM, Masalov DV, Burakov AM, et al.: A pilot study of memantine effects on protracted withdrawal (syndrome of anhedonia) in heroin addicts. Addict Disord Their Treatment. 2002; 1: 143-146.

Comer SD, Sullivan MA: Memantine produces modest reductions in heroin-induced subjective responses in human research volunteers. Psychopharmacology (Berl). 2007; 193(2): 235-245.

Ganguly KK: Pattern and process of drug and alcohol use in India. ICMR Bull. 2008; 38(1-3): 1-8.

Gutstein HB, Akil H: Opioid analgesic. In Hardman JG, Limbird LE (eds.): The Pharmacological Basis of Therapeutics. New York: Macmillan Publication, 2001: 569-619.

Handelsman L, Cochrane KJ, Aronson MJ, et al.: Two new rating scales for opiate withdrawal. Am J Drug Alcohol Abuse. 1987; 13(3): 293-308.

De S, Jain R, Ray R, et al.: Assessment of differential doses of buprenorphine for long term pharmacotherapy among opiate dependent subjects. Indian J Physiol Pharmacol. 2008; 52(1): 53-63.

Naidu AN, Rao NP: Body mass index: A measure of the nutritional status in Indian populations. Eur J Clin Nutr. 1994; 48 (Suppl 3): S131-S140.

Hossain KJ, Kamal MM, Ahsan M, et al.: Serum antioxidant micromineral (Cu, Zn, Fe) status of drug dependent subjects: Influence of illicit drugs and lifestyle. Subst Abuse Treat Prev Policy. 2007; 2: 12.

Jain R: Analytical methods. In Jain R (ed.): Detection of Drugs of Abuse in Body Fluids: A Manual for Laboratory Personnel. New Delhi, India: Drug Dependence Treatment Centre, All India Institute of Medical Sciences, 1998: 18-44.

Harper I: Temgesic abuse. N Z Med J. 1983; 96(741): 777.

Kosten TR, Kleber HD: Strategies to improve compliance with narcotic antagonists. Am J Drug Alcohol Abuse. 1984; 10(2): 249-266.

O’Connor JJ, Maloney E, Travers R, et al.: Buprenorphine abuse among opiate addicts. Br J Addict. 1988; 83(9): 1085-1087.

Chowdhury AN, Chowdhury S: Buprenorphine abuse: Report from India. Br J Addict. 1990; 85(10): 1349-1350.

Bedi NS, Ray R, Jain R, et al.: Abuse liability of buprenorphine–A study among experienced drug users. Indian J Physiol Pharmacol. 1998; 42(1): 95-100.

Gowing L, Ali R, White J: Buprenorphine for the management of opioid withdrawal. Cochrane Database Syst Rev. 2006; (2): CD002025.



How to Cite

Jain, MD, K., R. Jain, PhD, FRSC Chem, and A. Dhawan, MD. “A Double-Blind, Double-Dummy, Randomized Controlled Study of Memantine Versus Buprenorphine in Naloxone-Precipitated Acute Withdrawal in Heroin Addicts”. Journal of Opioid Management, vol. 7, no. 1, Jan. 2018, pp. 11-20, doi:10.5055/jom.2011.0044.