Comorbid alcohol use disorder and posttraumatic stress disorder: A proof-of-concept randomized placebo-controlled trial of buprenorphine and naltrexone combination treatment.
alcohol abuse
alcohol dependence
alcohol use disorder
buprenorphine
kappa-opioid receptor
naltrexone
posttraumatic stress disorder
Journal
Alcohol, clinical & experimental research
ISSN: 2993-7175
Titre abrégé: Alcohol Clin Exp Res (Hoboken)
Pays: United States
ID NLM: 9918609780906676
Informations de publication
Date de publication:
Sep 2023
Sep 2023
Historique:
revised:
21
06
2023
received:
30
01
2023
accepted:
13
07
2023
medline:
20
7
2023
pubmed:
20
7
2023
entrez:
19
7
2023
Statut:
ppublish
Résumé
Effective pharmacologic treatments for comorbid alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) are lacking. Kappa (κ) opioid receptor antagonists may address this unmet need. Buprenorphine is a κ-opioid antagonist and a partial agonist of mu (μ) opioid receptors. Whereas naltrexone blocks all μ-mediated effects combining it with buprenorphine yields a pharmacologic net effect of opioid receptor antagonism. Because no κ-opioid receptor antagonist it available for clinical use, we tested this combination in a proof-of-concept study. Consenting participants were enrolled in a Phase II, multisite, double-blind, randomized, placebo-controlled trial evaluating the effectiveness of sublingual (SL) buprenorphine combined with extended-release (XR) injectable naltrexone for the treatment of comorbid AUD and PTSD. Eligible participants (n = 75) were randomized (1:1:1) to receive either buprenorphine 2 mg/day plus naltrexone-XR (n = 35), buprenorphine 8 mg/day plus naltrexone-XR (n = 6) or SL plus injectable placebo (n = 34) for 12 weeks. The buprenorphine 8 mg/day plus naltrexone-XR arm was dropped early in the trial due to the negative impact of COVID-19 on enrollment. A binary primary outcome of response at week 8 was defined as a decrease from baseline of ≥10 points on the past week Clinician-Administered PTSD Scale (CAPS-5) and a reduction of ≥1 of past month alcohol risk level, as defined by the World Health Organization (WHO) and measured by the Timeline Follow-Back. Based on the results of a futility analysis, enrollment was stopped prior to reaching the initial goal of 90 participants. At the week eight primary timepoint, there were no statistically significant differences between buprenorphine plus naltrexone-XR and placebo group for the primary composite outcome (OR = 0.63; p-value = 0.52), or the subcomponents of the PTSD outcome (OR = 0.76; p-value = 0.69) and AUD outcome (OR = 0.17; p-value = 0.08). The placebo arm had a significantly higher proportion of participants with ≥1 WHO risk level reduction than the buprenorphine plus naltrexone-XR arm (OR = 0.18, p value = 0.02). This is the first study to evaluate the potential of κ-opioid receptor antagonism for the treatment of comorbid AUD and PTSD. The combination of buprenorphine and naltrexone-XR showed no significant improvement over placebo for the composite, PTSD, or alcohol measures.
Sections du résumé
BACKGROUND
BACKGROUND
Effective pharmacologic treatments for comorbid alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) are lacking. Kappa (κ) opioid receptor antagonists may address this unmet need. Buprenorphine is a κ-opioid antagonist and a partial agonist of mu (μ) opioid receptors. Whereas naltrexone blocks all μ-mediated effects combining it with buprenorphine yields a pharmacologic net effect of opioid receptor antagonism. Because no κ-opioid receptor antagonist it available for clinical use, we tested this combination in a proof-of-concept study.
METHODS
METHODS
Consenting participants were enrolled in a Phase II, multisite, double-blind, randomized, placebo-controlled trial evaluating the effectiveness of sublingual (SL) buprenorphine combined with extended-release (XR) injectable naltrexone for the treatment of comorbid AUD and PTSD. Eligible participants (n = 75) were randomized (1:1:1) to receive either buprenorphine 2 mg/day plus naltrexone-XR (n = 35), buprenorphine 8 mg/day plus naltrexone-XR (n = 6) or SL plus injectable placebo (n = 34) for 12 weeks. The buprenorphine 8 mg/day plus naltrexone-XR arm was dropped early in the trial due to the negative impact of COVID-19 on enrollment. A binary primary outcome of response at week 8 was defined as a decrease from baseline of ≥10 points on the past week Clinician-Administered PTSD Scale (CAPS-5) and a reduction of ≥1 of past month alcohol risk level, as defined by the World Health Organization (WHO) and measured by the Timeline Follow-Back.
RESULTS
RESULTS
Based on the results of a futility analysis, enrollment was stopped prior to reaching the initial goal of 90 participants. At the week eight primary timepoint, there were no statistically significant differences between buprenorphine plus naltrexone-XR and placebo group for the primary composite outcome (OR = 0.63; p-value = 0.52), or the subcomponents of the PTSD outcome (OR = 0.76; p-value = 0.69) and AUD outcome (OR = 0.17; p-value = 0.08). The placebo arm had a significantly higher proportion of participants with ≥1 WHO risk level reduction than the buprenorphine plus naltrexone-XR arm (OR = 0.18, p value = 0.02).
CONCLUSIONS
CONCLUSIONS
This is the first study to evaluate the potential of κ-opioid receptor antagonism for the treatment of comorbid AUD and PTSD. The combination of buprenorphine and naltrexone-XR showed no significant improvement over placebo for the composite, PTSD, or alcohol measures.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1756-1772Subventions
Organisme : U.S. Army Medical Research Acquisition Activity
ID : W81XWH-15-2-0077
Informations de copyright
© 2023 The Authors. Alcohol: Clinical and Experimental Research published by Wiley Periodicals LLC on behalf of Research Society on Alcohol. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.
Références
Almatroudi, A., Husbands, S.M., Bailey, C.P. & Bailey, S.J. (2015) Combined administration of buprenorphine and naltrexone produces antidepressant-like effects in mice. Journal of Psychopharmacology, 29(7), 812-821.
American Psychiatric Association. (2013) Diagnostic and statistical manual of mental disorders, 5th edition. Washington, DC: American Psychiatric Publication.
Anderson, R.I. & Becker, H.C. (2017) Role of the dynorphin/kappa opioid receptor system in the motivational effects of ethanol. Alcoholism: Clinical and Experimental Research, 41(8), 1402-1418.
Benjamini, Y. & Hochberg, Y. (1995) Controlling the false discovery rate: a practical and powerful approach to multiple testing. Journal of the Royal Statistical Society, Series B, 57, 289-300.
Blanco, C., Xu, Y., Brady, K., Pérez-Fuentes, G., Okuda, M. & Wang, S. (2013) Comorbidity of posttraumatic stress disorder with alcohol dependence among US adults: results from National Epidemiological Survey on alcohol and related conditions. Drug and Alcohol Dependence, 132(3), 630-638.
Blevins, C.A., Weathers, F.W., Davis, M.T., Witte, T.K. & Domino, J.L. (2015) The posttraumatic stress disorder checklist for DSM-5 (PCL-5): development and initial psychometric evaluation. Journal of Traumatic Stress, 28(6), 489-498.
Carlezon, W.A., Jr., Beguin, C., Knoll, A.T. & Cohen, B.M. (2009) Kappa-opioid ligands in the study and treatment of mood disorders. Pharmacology & Therapeutics, 123(3), 334-343.
Carlezon, W.A., Jr. & Krystal, A.D. (2016) Kappa-opioid antagonists for psychiatric disorders: from bench to clinical trials. Depression and Anxiety, 33(10), 895-906.
Chandran, K., Mazer-Amirshahi, M., Shankar, N., Desale, S., Nelson, L. & Mete, M. (2021) Impact of COVID-19 pandemic on emergency department substance use screens and overdose presentations. American Journal of Emergency Medicine, 50, 472-476.
Chavkin, C. & Koob, G.F. (2016) Dynorphin, dysphoria, and dependence: the stress of addiction. Neuropsychopharmacology, 41(1), 373-374.
Debell, F., Fear, N.T., Head, M., Batt-Rawden, S., Greenberg, N., Wessely, S. et al. (2014) A systematic review of the comorbidity between PTSD and alcohol misuse. Social Psychiatry and Psychiatric Epidemiology, 49(9), 1401-1425.
Del Re, A.C., Maisel, N., Blodgett, J.C., Wilbourne, P. & Finney, J.W. (2013) Placebo group improvement in trials of pharmacotherapies for alcohol use disorders: a multivariate meta-analysis examining change over time. Journal of Clinical Psychopharmacology, 33(5), 649-657.
Domi, E., Barbier, E., Augier, E., Augier, G., Gehlert, D., Barchiesi, R. et al. (2018) Preclinical evaluation of the kappa-opioid receptor antagonist CERC-501 as a candidate therapeutic for alcohol use disorders. Neuropsychopharmacology, 43(9), 1805-1812.
Emerson, M.A., Moore, R.S. & Caetano, R. (2017) Association between lifetime posttraumatic stress disorder and past year alcohol use disorder among American Indians/Alaska natives and non-Hispanic whites. Alcoholism, Clinical and Experimental Research, 41(3), 576-584.
Enck, P., Benedetti, F. & Schedlowski, M. (2008) New insights into the placebo and nocebo responses. Neuron, 59(2), 195-206.
Fava, M., Memisoglu, A., Thase, M.E., Bodkin, J.A., Trivedi, M.H., de Somer, M. et al. (2016) Opioid modulation with buprenorphine/samidorphan as adjunctive treatment for inadequate response to antidepressants: a randomized double-blind placebo-controlled trial. American Journal of Psychiatry, 173(5), 499-508.
Goldstein, R.B., Smith, S.M., Chou, S.P., Saha, T.D., Jung, J., Zhang, H. et al. (2016) The epidemiology of DSM-5 posttraumatic stress disorder in the United States: results from the National Epidemiologic Survey on alcohol and related conditions-III. Social Psychiatry and Psychiatric Epidemiology, 51(8), 1137-1148.
Grant, B.F., Goldstein, R.B., Saha, T.D., Chou, S.P., Jung, J., Zhang, H. et al. (2015) Epidemiology of DSM-5 alcohol use disorder: results from the national epidemiologic survey on alcohol and related conditions III. JAMA Psychiatry, 72(8), 757-766.
Hagman, B.T., Falk, D., Litten, R. & Koob, G.F. (2022) Defining recovery from alcohol use disorder: development of an NIAAA research definition. The American Journal of Psychiatry, 179(11), 807-813.
Hodgins, G.E., Blommel, J.G., Dunlop, B.W., Iosifescu, D., Mathew, S.J., Neylan, T.C. et al. (2018) Placebo effects across self-report, clinician rating, and objective performance tasks among women with post-traumatic stress disorder: investigation of placebo response in a pharmacological treatment study of post-traumatic stress disorder. Journal of Clinical Psychopharmacology, 38(3), 200-206.
Jones, J.D., Babalonis, S., Marcus, R., Vince, B., Kelsh, D., Lofwall, M.R. et al. (2020) A randomized, double-blind, placebo-controlled study of the kappa opioid receptor antagonist, CERC-501, in a human laboratory model of smoking behavior. Addiction Biology, 25(4), e12799.
Killgore, W.D.S., Cloonan, S.A., Taylor, E.C., Lucas, D.A. & Dailey, N.S. (2021) Alcohol dependence during COVID-19 lockdowns. Psychiatry Research, 296, 113676.
Kissler, J.L., Sirohi, S., Reis, D.J., Jansen, H.T., Quock, R.M., Smith, D.G. et al. (2014) The one two punch of alcoholism: role of central amygdala dynorphins/kappa-opioid receptors. Biological Psychiatry, 75(10), 774-782.
Knox, J., Wall, M., Witkiewitz, K., Kranzler, H.R., Falk, D., Litten, R. et al. (2018) Reduction in nonabstinent WHO drinking risk levels and change in risk for liver disease and positive AUDIT-C scores: prospective 3-year follow-up results in the U.S. general population. Alcoholism, Clinical and Experimental Research, 42(11), 2256-2265.
Kroenke, K., Spitzer, R.L. & Williams, J.B. (2001) The PHQ-9: validity of a brief depression severity measure. Journal of General Internal Medicine, 16(9), 606-613.
Lake, E., Mitchell, B., Shorter, D., Kosten, T.R., Domingo, C.B. & Walder, A. (2019) Buprenorphine for the treatment of posttraumatic stress disorder. The American Journal on Addictions, 28(2), 86-91.
Land, B.B., Bruchas, M.R., Lemos, J.C., Xu, M., Melief, E. & Chavkin, J.C. (2008) The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system. Journal of Neuroscience, 28(2), 407-414.
Leggio, L., Falk, D.E., Ryan, M.L., Fertig, J. & Litten, R.Z. (2020) Medication development for alcohol use disorder: a focus on clinical studies. Handbook of Experimental Pharmacology, 258, 443-462.
Ling, W., Hillhouse, M.P., Saxon, A.J., Mooney, L.J., Thomas, C.M., Ang, A. et al. (2016) Buprenorphine + naloxone plus naltrexone for the treatment of cocaine dependence: the cocaine use reduction with buprenorphine (CURB) study. Addiction, 111(8), 1416-1427.
Litman, R.E., Sorantin, P. & Acevedo-Diaz, E.E. (2021) Drug development for mental illness: how psychiatry clinical trial sites are meeting the challenge of the COVID-19 pandemic. Innovations in Clinical Neuroscience, 18(1-3), 35-38.
Litten, R.Z., Castle, I.J., Falk, D., Ryan, M., Fertig, J., Chen, C.M. et al. (2013) The placebo effect in clinical trials for alcohol dependence: an exploratory analysis of 51 naltrexone and acamprosate studies. Alcoholism, Clinical and Experimental Research, 37(12), 2128-2137.
Litten, R.Z., Egli, M., Heilig, M., Cui, C., Fertig, J.B., Ryan, M.L. et al. (2012) Medications development to treat alcohol dependence: a vision for the next decade. Addiction Biology, 17(3), 513-527.
McCullagh, P. & Nelder, J.A. (1989) Generalized linear models, 2nd edition. Boca Raton, Florida: Chapman & Hall/CRC Press.
Murthy, P. & Narasimha, V.L. (2021) Effects of the COVID-19 pandemic and lockdown on alcohol use disorders and complications. Current Opinion in Psychiatry, 34(4), 376-385.
Naganawa, M., Dickinson, G.L., Zheng, M.Q., Henry, S., Vandenhende, F., Witcher, J. et al. (2016) Receptor occupancy of the κ-opioid antagonist LY2456302 measured with positron emission tomography and the novel radiotracer 11C-LY2795050. The Journal of Pharmacology and Experimental Therapeutics, 356(2), 260-266.
Peltier, M. R., Verplaetse, T. L., Mineur, Y. S., Petrakis, I. L., Cosgrove, K. P., Picciotto, M. R., & McKee, S. A. (2019). Sex differences in stress-related alcohol use. Neurobiology of Stress, 10, 100149. Available from: https://doi.org/10.1016/j.ynstr.2019.100149
Palmisano, A.N., Fogle, B.M., Tsai, J., Petrakis, I.L. & Pietrzak, R.H. (2021) Disentangling the association between PTSD symptom heterogeneity and alcohol use disorder: results from the 2019-2020 National Health and resilience in veterans study. Journal of Psychiatric Research, 142, 179-187.
Petrakis, I.L. & Simpson, T.L. (2017) Posttraumatic stress disorder and alcohol use disorder: a critical review of pharmacologic treatments. Alcoholism, Clinical and Experimental Research, 41(2), 226-237.
Pettinati, H.M., Weiss, R.D., Dundon, W., Miller, W.R., Donovan, D., Ernst, D.B. et al. (2005) A structured approach to medical management: a psychosocial intervention to support pharmacotherapy in the treatment of alcohol dependence. Journal of Studies on Alcohol, Supplement, 15, 170-169.
Ramalho, R. (2020) Alcohol consumption and alcohol-related problems during the COVID-19 pandemic: a narrative review. Australasian Psychiatry, 28(5), 524-526.
Rojas, S.M., Bujarski, S., Babson, K.A., Dutton, C.E. & Feldner, M.T. (2014) Understanding PTSD comorbidity and suicidal behavior: associations among histories of alcohol dependence, major depressive disorder, and suicidal ideation and attempts. Journal of Anxiety Disorders, 28(3), 318-325.
Rorick-Kehn, L.M., Witkin, J.M., Statnick, M.A., Eberle, E.L., McKinzie, J.H., Kahl, S.D. et al. (2014) LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders. Neuropharmacology, 77, 131-144.
Schafer, J.L. & Graham, J.W. (2002) Missing data: our view of the state of the art. Psychological Methods, 7(2), 147-177.
Scherrer, B., Guiraud, J., Addolorato, G., Aubin, H.J., de Bejczy, A., Benyamina, A. et al. (2021) Baseline severity and the prediction of placebo response in clinical trials for alcohol dependence: a meta-regression analysis to develop an enrichment strategy. Alcoholism, Clinical and Experimental Research, 45(9), 1722-1734.
Schnurr, P.P., Chard, K.M., Ruzek, J.I., Chow, B.K., Resick, P.A., Foa, E.B. et al. (2022) Comparison of prolonged exposure vs cognitive processing therapy for treatment of posttraumatic stress disorder among US veterans: a randomized clinical trial. JAMA Network Open, 5(1), e2136921.
Seal, K.H., Maguen, S., Bertenthal, D., Batki, S.L., Striebel, J., Stein, M.B. et al. (2016) Observational evidence for buprenorphine's impact on posttraumatic stress symptoms in veterans with chronic pain and opioid use disorder. The Journal of Clinical Psychiatry, 77(9), 1182-1188.
Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E. et al. (1998) The Mini-international neuropsychiatric interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. Journal of Clinical Psychiatry, 18(59 Suppl 20), 22-33;quiz 34-57.
Smith, N.D.L. & Cottler, L.B. (2018) The epidemiology of post-traumatic stress disorder and alcohol use disorder. Alcohol Research: Current Reviews, 39(2), 113-120.
Sobell, L.C. & Sobell, M.B. (1992) Timeline follow-back. In: Litten, R.Z. & Allen, J.P. (Eds.) Measuring alcohol consumption. Totowa, NJ: Humana Press.
Stanciu, C.N., Glass, O.M. & Penders, T.M. (2017) Use of buprenorphine in treatment of refractory depression-a review of current literature. Asian Journal of Psychiatry, 26, 94-98.
Straus, E., Norman, S.B. & Pietrzak, R.H. (2020) Determinants of new-onset alcohol use disorder in U.S. military veterans: results from the National Health and resilience in veterans study. Addictive Behaviors, 105, 106313.
Sullivan, J.T., Sykora, K., Schneiderman, J., Naranjo, C.A. & Sellers, E.M. (1989) Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). British Journal of Addiction, 84(11), 1353-1357.
Tan, L.A., Gajipara, N., Sun, L., Bacolod, M., Zhou, Y., Namchuk, M. et al. (2022) In vivo characterization of the opioid receptor-binding profiles of samidorphan and naltrexone in rats: comparisons at clinically relevant concentrations. Neuropsychiatric Disease and Treatment, 18, 2497-2506.
Tanielian, T. & Jaycox, L.H. (Eds.). (2008) Invisible wounds of war: psychological and cognitive injuries, their consequences, and services to assist recovery. Santa Monica, CA: RAND Corporation.
Verplaetse, T.L., McKee, S.A. & Petrakis, I.L. (2018) Pharmacotherapy for co-occurring alcohol use disorder and post-traumatic stress disorder: targeting the opioidergic, noradrenergic, serotonergic, and GABAergic/glutamatergic systems. Alcohol Research, 39(2), 193-205.
Ware, J., Kosinski, M. & Keller, S.D. (1996) A 12-item short-form health survey: construction of scales and preliminary tests of reliability and validity. Medical Care, 34, 220-233.
Weathers, F.W., Bovin, M.J., Lee, D.J., Sloan, D.M., Schnurr, P.P., Kaloupek, D.G. et al. (2018) The clinician-administered PTSD scale for DSM-5 (CAPS-5): development and initial psychometric evaluation in military veterans. Psychological Assessment, 30, 383-395.
Wee, S. & Koob, G.F. (2010) The role of the dynorphin-kappa opioid system in the reinforcing effects of drugs of abuse. Psychopharmacology, 210(2), 121-135.
Wee, S., Leandro, F., Vendruscolo, F., Misra, K.K., Schlosburg, J.E. & Koob, G.F. (2012) A combination of buprenorphine and naltrexone blocks compulsive cocaine intake in rodents without producing dependence. Science Translational Medicine, 4(146), 146.
Zhou, Y., Crowlet, R.S., Ben, K., Prisinzano, T.E. & Kreek, M.J. (2017) Synergistic blockade of alcohol escalation drinking in mice by a combination of novel kappa opioid receptor agonist Mesyl Salvinorin B and naltrexone. Brain Research, 1662, 75-86.