Naltrexone treatment for prolonged grief disorder: study protocol for a randomized, triple-blinded, placebo-controlled trial

James Gang, James Kocsis, Jonathan Avery, Paul K Maciejewski, Holly G Prigerson, James Gang, James Kocsis, Jonathan Avery, Paul K Maciejewski, Holly G Prigerson

Abstract

Background: There is a lack of effective pharmacotherapy for prolonged grief disorder (PGD). Evidence suggests that the neurobiology of PGD involves the same circuitry as the reward pathway. Based upon this evidence, we hypothesize that PGD can be conceptualized as a disorder of addiction and therefore could benefit from being treated with medications that are currently used to treat such disorders. One such medication is naltrexone, which is currently used to treat alcohol and opioid dependence. Oral naltrexone was chosen for its mechanism of action, safety, and convenience. The primary aim of this study is to establish the efficacy of using oral naltrexone as a pharmacological treatment for PGD. Specifically, we hypothesize that participants receiving naltrexone will demonstrate reduced PGD symptoms when compared to placebo.

Methods/design: This is a randomized, placebo-controlled, triple-blinded (to healthcare professionals/study staff, participants, and data analysts) study in which we propose to enroll 48 participants who meet criteria for Prolonged Grief Disorder (PGD). Participants will be randomly assigned to the naltrexone 50 mg oral arm or placebo arm; medications will be over-encapsulated to appear identical. Participants will take their assigned medication for 8 weeks, with clinic visits every 4 weeks to assess symptom severity, social closeness, and adverse reactions. Weekly surveys of Prolonged Grief-13-Revised (PG-13-R) will be used to relate naltrexone use to changes in PGD symptom severity. Follow-up 4 weeks after their last visit will assess the longevity of treatment, as well as any lingering adverse reactions.

Discussion: This study is the first to investigate the use of oral naltrexone as pharmacological treatment for PGD. The acute and debilitating nature of the disorder, in addition to the increased risk of comorbidities, highlights the need for pharmacological treatment like naltrexone that can act more rapidly, may help those for whom psychotherapy may not be effective, and/or may augment psychotherapy to promote PGD symptom grief resolution.

Trial registration: ClinicalTrials.gov NCT04547985 . Registered on 8/31/2020.

Keywords: Naltrexone; Pharmacological treatment; Prolonged grief disorder; Randomized control trial.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schema
Fig. 2
Fig. 2
Consent Form
Fig. 3
Fig. 3
Naltrexone patient information sheet

References

    1. Maercker A, Brewin CR, Bryant RA, Cloitre M, van Ommeren M, Jones LM, et al. Diagnosis and classification of disorders specifically associated with stress: proposals for ICD-11. World Psychiatry. 2013;12(3):198–206. doi: 10.1002/wps.20057.
    1. ICD-11 for Mortality and Morbidity Statistics. . Accessed Nov 2020.
    1. American Psychiatric Association. . Accessed Nov 2020.
    1. Prigerson HG, Boelen PA, Xu J, Smith KV, Maciejewski PK. Validation of the new DSM-5-TR criteria for prolonged grief disorder and the PG-13-Revised (PG-13-R) scale. World Psychiatry. 2021;20(1):96–106.
    1. Prigerson HG, Horowitz MJ, Jacobs SC, Parkes CM, Aslan M, Goodkin K, et al. Prolonged grief disorder: Psychometric validation of criteria proposed for DSM-V and ICD-11. PLoS Med. 2009;6(8):e1000121–e100012e. doi: 10.1371/journal.pmed.1000121.
    1. Trevino KM, Litz B, Papa A, Maciejewski PK, Lichtenthal W, Healy C, et al. Bereavement challenges and their relationship to physical and psychological adjustment to loss. J Palliat Med. 2018;21(4):479–488. doi: 10.1089/jpm.2017.0386.
    1. Lannen PK, Wolfe J, Prigerson HG, Onelov E, Kreicbergs UC. Unresolved grief in a national sample of bereaved parents: impaired mental and physical health 4 to 9 years later. J Clin Oncol. 2008;26(36):5870–5876. doi: 10.1200/JCO.2007.14.6738.
    1. Prigerson HG, Bierhals AJ, Kasl SV, Reynolds CF, 3rd, Shear MK, Day N, et al. Traumatic grief as a risk factor for mental and physical morbidity. Am J Psychiatry. 1997;154(5):616–623. doi: 10.1176/ajp.154.5.616.
    1. Holland JM, Graves S, Klingspon KL, Rozalski V. Prolonged grief symptoms related to loss of physical functioning: examining unique associations with medical service utilization. Disabil Rehabil. 2016;38(3):205–210. doi: 10.3109/09638288.2015.1031830.
    1. Shear K, Frank E, Houck PR, Reynolds CF., 3rd Treatment of complicated grief: a randomized controlled trial. JAMA. 2005;293(21):2601–2608. doi: 10.1001/jama.293.21.2601.
    1. Bryant RA, Kenny L, Joscelyne A, Rawson N, Maccallum F, Cahill C, et al. Treating prolonged grief disorder: a randomized clinical trial. JAMA Psychiatry. 2014;71(12):1332–1339. doi: 10.1001/jamapsychiatry.2014.1600.
    1. Bui E, Nadal-Vicens M, Simon NM. Pharmacological approaches to the treatment of complicated grief: rationale and a brief review of the literature. Dialogues Clin Neurosci. 2012;14(2):149–157. doi: 10.31887/DCNS.2012.14.2/ebui.
    1. Zygmont M, Prigerson HG, Houck PR, Miller MD, Shear MK, Jacobs S, et al. A post hoc comparison of paroxetine and nortriptyline for symptoms of traumatic grief. J Clin Psychiatry. 1998;59(5):241–245. doi: 10.4088/JCP.v59n0507.
    1. Reynolds CF, 3rd, Miller MD, Pasternak RE, Frank E, Perel JM, Cornes C, et al. Treatment of bereavement-related major depressive episodes in later life: a controlled study of acute and continuation treatment with nortriptyline and interpersonal psychotherapy. Am J Psychiatry. 1999;156(2):202–208.
    1. Bryant RA, Andrew E, Korgaonkar MS. Distinct neural mechanisms of emotional processing in prolonged grief disorder. Psychol Med. 2020:1–9.
    1. Kakarala SE, Roberts KE, Rogers M, Coats T, Falzarano F, Gang J, et al. The neurobiological reward system in prolonged grief disorder (PGD): a systematic review. Psychiatry Res Neuroimaging. 2020;303:111135. doi: 10.1016/j.pscychresns.2020.111135.
    1. Latham AE, Prigerson HG. Suicidality and bereavement: complicated grief as psychiatric disorder presenting greatest risk for suicidality. Suicide Life Threat Behav. 2004;34(4):350–362. doi: 10.1521/suli.34.4.350.53737.
    1. O'Connor MF, Wellisch DK, Stanton AL, Eisenberger NI, Irwin MR, Lieberman MD. Craving love? Enduring grief activates brain's reward center. Neuroimage. 2008;42(2):969–972. doi: 10.1016/j.neuroimage.2008.04.256.
    1. Klein JW. Pharmacotherapy for substance use disorders. Med Clin North Am. 2016;100(4):891–910. doi: 10.1016/j.mcna.2016.03.011.
    1. Stahl SM. Stahl's essential psychopharmacology: Prescriber's guide. 5. New York: Cambridge University Press; 2014.
    1. Inagaki TK, Ray LA, Irwin MR, Way BM, Eisenberger NI. Opioids and social bonding: naltrexone reduces feelings of social connection. Soc Cogn Affect Neurosci. 2016;11(5):728–735. doi: 10.1093/scan/nsw006.
    1. Inagaki TK, Hazlett LI, Andreescu C. Opioids and social bonding: effect of naltrexone on feelings of social connection and ventral striatum activity to close others. J Exp Psychol Gen. 2020;149(4):732–745. doi: 10.1037/xge0000674.
    1. Hendershot CS, Wardell JD, Samokhvalov AV, Rehm J. Effects of naltrexone on alcohol self-administration and craving: meta-analysis of human laboratory studies. Addict Biol. 2017;22(6):1515–1527. doi: 10.1111/adb.12425.
    1. Anton RF. Naltrexone for the management of alcohol dependence. N Engl J Med. 2008;359(7):715–721. doi: 10.1056/NEJMct0801733.
    1. Stahl ST, Schulz R. Changes in routine health behaviors following late-life bereavement: a systematic review. J Behav Med. 2014;37(4):736–755. doi: 10.1007/s10865-013-9524-7.
    1. Boelen PA, van de Schoot R, van den Hout MA, de Keijser J, van den Bout J. Prolonged grief disorder, depression, and posttraumatic stress disorder are distinguishable syndromes. J Affect Disord. 2010;125(1–3):374–378. doi: 10.1016/j.jad.2010.01.076.
    1. Aron A, Aron EN, Smollan D. Inclusion of other in the self scale and the structure of interpersonal closeness. J Pers Soc Psychol. 1992;63(4):596–612. doi: 10.1037/0022-3514.63.4.596.
    1. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, et al. The Columbia-suicide severity rating scale: initial validity and internal consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011;168(12):1266–1277. doi: 10.1176/appi.ajp.2011.10111704.
    1. Maciejewski PK, Maercker A, Boelen PA, Prigerson HG. "Prolonged grief disorder" and "persistent complex bereavement disorder", but not "complicated grief", are one and the same diagnostic entity: an analysis of data from the Yale bereavement study. World Psychiatry. 2016;15(3):266–275. doi: 10.1002/wps.20348.
    1. Schafer JL, Olsen MK. Multiple imputation for multivariate missing-data problems: a data Analyst's perspective. Multivariate Behav Res. 1998;33(4):545–571. doi: 10.1207/s15327906mbr3304_5.
    1. Information for the user. 2019. . Accessed Nov 2020.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere