Naltrexone Implant for Opioid Use Disorder
Abstract
:1. Introduction
2. Chronic Opiate Use
2.1. Opioid Dependency Risk Factors
2.2. Opioid Dependency Outcomes
2.3. Opioid Dependency Prevention
3. Current Treatment of Opioid Use Disorder (OUD)
4. Naltrexone Implant
Mechanism of Action
5. Pharmacokinetics/Pharmacodynamics
6. Safety and Efficacy
6.1. Safety
6.2. Efficacy
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Wilson, N.; Kariisa, M.; Seth, P.; Smith, H.; Davis, N.L. Drug and Opioid-Involved Overdose Deaths—United States, 2017–2018. MMWR Morb. Mortal. Wkly. Rep. 2020, 69, 290–297. [Google Scholar] [CrossRef] [Green Version]
- Jones, M.R.; Viswanath, O.; Peck, J.; Kaye, A.D.; Gill, J.S.; Simopoulos, T.T. A Brief History of the Opioid Epidemic and Strategies for Pain Medicine. Pain Ther. 2018, 7, 13–21. [Google Scholar] [CrossRef] [Green Version]
- Products-Vital Statistics Rapid Release-Provisional Drug Overdose Data. Available online: https://www.cdc.gov/nchs/nvss/vsrr/drug-overdose-data.htm (accessed on 23 December 2020).
- Skolnick, P. The Opioid Epidemic: Crisis and Solutions. In Annual Review of Pharmacology and Toxicology; Annual Reviews Inc.: Palo Alto, CA, USA, 2018; Volume 58, pp. 143–159. [Google Scholar]
- Wilkerson, R.G.; Kim, H.K.; Windsor, T.A.; Mareiniss, D.P. The Opioid Epidemic in the United States. In Emergency Medicine Clinics of North America; W.B. Saunders: Philadelphia, PA, USA, 2016; Volume 34, pp. e1–e23. [Google Scholar]
- Manchikanti, L.; Kaye, A.M.; Kaye, A.D. Current State of Opioid Therapy and Abuse. Current Pain Headache Rep. 2016, 20, 34. [Google Scholar] [CrossRef]
- How Effective are Medications to Treat Opioid Use Disorder?|National Institute on Drug Abuse (NIDA). Available online: https://www.drugabuse.gov/publications/research-reports/medications-to-treat-opioid-addiction/efficacy-medications-opioid-use-disorder (accessed on 21 November 2020).
- Green, J. Epidemiology of Opioid Abuse and Addiction. J. Emerg. Nurs. 2017, 43, 106–113. [Google Scholar] [CrossRef]
- Zhao, S.; Chen, F.; Feng, A.; Han, W.; Zhang, Y. Risk Factors and Prevention Strategies for Postoperative Opioid Abuse; Pain Research and Management; Hindawi Limited: London, UK, 2019; Volume 2019. [Google Scholar]
- Webster, L.R. Risk Factors for Opioid-Use Disorder and Overdose. Anesthesia and Analgesia; Lippincott Williams and Wilkins: Philadelphia, PA, USA, 2017; Volume 125, pp. 1741–1748. [Google Scholar]
- Bohnert, A.S.B.; Ilgen, M.A. Understanding Links among Opioid Use, Overdose, and Suicide. N. Engl. J. Med. 2019, 380, 71–79. [Google Scholar] [CrossRef]
- Rudd, R.A.; Seth, P.; David, F.; Scholl, L. Increases in Drug and Opioid-Involved Overdose Deaths—United States, 2010–2015. MMWR Morb. Mortal. Wkly. Rep. 2016, 65, 1445–1452. [Google Scholar] [CrossRef] [Green Version]
- Nicholas, E. Hagemeier. Introduction to the Opioid Epidemic: The Economic Burden on the Healthcare System and Impact on Quality of Life | AJMC. Am. J. Manag. Care 2018, 24, 200–206. [Google Scholar]
- Wheeler, E.; Jones, T.S.; Gilbert, M.K.; Davidson, P.J.; Centers for Disease Control and Prevention (CDC). Opioid Overdose Prevention Programs Providing Naloxone to Laypersons-United States, 2014. MMWR Morb. Mortal. Wkly. Rep. 2015, 64, 631–635. [Google Scholar]
- Mueller, S.R.; Walley, A.Y.; Calcaterra, S.L.; Glanz, J.M.; Binswanger, I.A. A Review of Opioid Overdose Prevention and Naloxone Prescribing: Implications for Translating Community Programming into Clinical Practice. In Substance Abuse; Routledge: London, UK, 2015; Volume 36, pp. 240–253. [Google Scholar]
- Olfson, M.; Wall, M.; Wang, S.; Crystal, S.; Blanco, C. Risks of fatal opioid overdose during the first year following nonfatal overdose. Drug Alcohol Depend. 2018, 190, 112–119. [Google Scholar] [CrossRef]
- Wang, S. Historical Review: Opiate Addiction and Opioid Receptors. In Cell Transplantation; SAGE Publications Ltd.: Southend Oaks, CA, USA, 2019; Volume 28, pp. 233–238. [Google Scholar]
- Kosten, T.R.; Baxter, L.E. Review article: Effective management of opioid withdrawal symptoms: A gateway to opioid dependence treatment. In American Journal on Addictions; Wiley Blackwell: Hoboken, NJ, USA, 2019; Volume 28, pp. 55–62. [Google Scholar]
- Kosten, T.R.; George, T.P. The neurobiology of opioid dependence: Implications for treatment. Science & practice perspectives/a publication of the National Institute on Drug Abuse, National Institutes of Health. Sci. Pract. Perspect 2002, 1, 13–20. [Google Scholar]
- Abuse, S.; Health Services Administration M. Medications for Opioid Use Disorder TIP 63 TREATMENT IMPROVEMENT PROTOCOL For Healthcare and Addiction Professionals, Policymakers, Patients, and Families. Available online: https://www.surveymonkey.com/r/KAPPFS (accessed on 23 December 2020).
- Bart, G. Maintenance medication for opiate addiction: The foundation of recovery. J. Addict. Dis. 2012, 31, 207–225. [Google Scholar] [CrossRef] [Green Version]
- Davis, A.; Inturrisi, C. d-Methadone Blocks Morphine Tolerance andN-Methyl-d-Aspartate-Induced Hyperalgesia | Journal of Pharmacology and Experimental Therapeutics. J. Pharmacol. Exp. Ther. 1999, 289, 1048–1053. [Google Scholar]
- Ayanga, D.; Shorter, D.; Kosten, T.R. Update on pharmacotherapy for treatment of opioid use disorder. In Expert Opinion on Pharmacotherapy; Taylor and Francis Ltd.: Abingdon, UK, 2016; Volume 17, pp. 2307–2318. [Google Scholar]
- Gowing, L.; Farrell, M.; Ali, R.; White, J.M. Alpha2-adrenergic agonists for the management of opioid withdrawal. In Cochrane Database of Systematic Reviews; John Wiley and Sons Ltd.: Hoboken, NJ, USA, 2009. [Google Scholar]
- Kaye, A.D.; Banister, R.E.; Hoover, J.M.; Baluch, A.R.; Jacobs, S.; Shah, R.V. Chronic pain and ultrarapid opioid detoxification. Pain Pract. 2005, 5, 33–42. [Google Scholar] [CrossRef]
- Kaye, A.D.; Kaye, A.M.; Urman, R.D. Essentials of pharmacology for anesthesia, pain medicine, and critical care. In Essentials of Pharmacology for Anesthesia, Pain Medicine, and Critical Care; Springer: New York, NY, USA, 2015; pp. 1–904. [Google Scholar]
- Kaye, A.D.; Gevirtz, C.; Bosscher, H.A.; Duke, J.B.; Frost, E.A.; Richards, T.A.; Fields, A.M. Ultrarapid opiate detoxification: A review. Can. J. Anesth. Can. Anaesth. Soc. 2003, 50, 663–671. [Google Scholar] [CrossRef] [Green Version]
- Urman, W.; Gross, B.; Gevirtz, C.; Frost, E.; Kaye, A.D. Opiate Detoxification (Ultra Rapid Detoxification), an Update. In Anesthesia Outside of the Operating Room; Oxford Press: Oxford, UK, 2018. [Google Scholar]
- Kaye, A.; Gevirtz, C.; Bosscher, H.; Duke, J.; Richards, T.; Fields, A. A Complete Review of Ultra Rapid Opiate Detoxification. Can. J. Anaesth. 2003, 50, 663–671. [Google Scholar] [CrossRef] [Green Version]
- Sigmon, S.C.; Bisaga, A.; Nunes, E.V.; O’Connor, P.G.; Kosten, T.; Woody, G. Opioid detoxification and naltrexone induction strategies: Recommendations for clinical practice. Am. J. Drug Alcohol Abus. 2012, 38, 187–199. [Google Scholar] [CrossRef] [Green Version]
- Naltrexone Implant and How It Releases Medication into the Body. Available online: https://medlibrary.org/lib/rx/meds/naltrexone/ (accessed on 10 November 2020).
- Comer, S.D.; Collins, E.D.; Kleber, H.D.; Nuwayser, E.S.; Kerrigan, J.H.; Fischman, M.W. Depot naltrexone: Long-lasting antagonism of the effects of heroin in humans. Psychopharmacology 2002, 159, 351–360. [Google Scholar] [CrossRef]
- Hulse, G.K.; Morris, N.; Arnold-Reed, D.; Tait, R.J. Improving clinical outcomes in treating heroin dependence: Randomized, controlled trial of oral or implant naltrexone. Arch Gen Psychiatry 2009, 66, 1108–1115. [Google Scholar] [CrossRef] [Green Version]
- Naltrexone Implant Treatment for Alcohol and Opioid Addiction. Available online: https://rightpathaddictioncenters.com/naltrexone-implant/ (accessed on 10 November 2020).
- Ngo, H.T.T.; Arnold-Reed, D.E.; Hansson, R.C.; Tait, R.J.; Hulse, G.K. Blood naltrexone levels over time following naltrexone implant. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2008, 32, 23–28. [Google Scholar] [CrossRef]
- Naltrexone. DrugBank Online. Available online: https://go.drugbank.com/drugs/DB00704 (accessed on 5 November 2020).
- Naltrexone (Complete Pharmacy and Medical Solutions): FDA Package Insert. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/018932s017lbl.pdf (accessed on 7 November 2020).
- Naltrexone: Drug information-UpToDate. Available online: https://www.uptodate.com/contents/naltrexone-drug-information?search=naltrexone&source=panel_search_result&selectedTitle=1~98&usage_type=panel&kp_tab=drug_general&display_rank=1 (accessed on 7 November 2020).
- Naltrexone-Side effects. Available online: https://reference.medscape.com/drug/vivitrol-revia-naltrexone-343333 (accessed on 6 November 2020).
- DailyMed-NALTREXONE Implant. Available online: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=40b16844-bc1c-485e-aad3-2cb86e2eb009 (accessed on 20 November 2020).
- Williams, K.L.; Broadbear, J.H.; Woods, J.H. Noncontingent and Response-Contingent Intravenous Ethanol Attenuates the Effect of Naltrexone on Hypothalamic-Pituitary-Adrenal Activity in Rhesus Monkeys. Alcohol. Clin. Exp. Res. 2004, 28, 566–571. [Google Scholar] [CrossRef]
- Naltrexone Black Box Warning|SinclairMethod.Org. Available online: https://www.sinclairmethod.org/naltrexone-black-box-warning/#:~:text=Naltrexone%20does%20not%20appear%20to,experience%20symptoms%20of%20acute%20hepatitis. (accessed on 5 November 2020).
- Pharmacotherapy for Opioid Use Disorder-UpToDate. Available online: https://www.uptodate.com/contents/pharmacotherapy-for-opioid-use-disorder?search=Pharmacotherapy%20for%20Opioid%20use%20Disorder&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1 (accessed on 10 November 2020).
- Kunøe, N.; Lobmaier, P.; Ngo, H.; Hulse, G. Injectable and implantable sustained-release naltrexone in the treatment of opioid addiction. Br. J. Clin. Pharmacol. 2014, 77, 264–271. [Google Scholar] [CrossRef] [Green Version]
- Waal, H.; Frogopsahl, G.; Olsen, L.; Christophersen, A.S.; Mørland, J. Naltrexone Implants–Duration, Tolerability and Clinical Usefulness. European Addict. Res. 2006, 12, 138–144. [Google Scholar] [CrossRef]
- Olsen, L.; Christophersen, A.S.; Frogopsahl, G.; Waal, H.; Mørland, J. Plasma concentrations during naltrexone implant treatment of opiate-dependent patients. Br. J. Clin. Pharmacol. 2004, 58, 219–222. [Google Scholar] [CrossRef] [Green Version]
- Yoburn, B.C.; Cohen, A.H.; Inturrisi, C.E. Pharmacokinetics and pharmacodynamics of subcutaneous naltrexone pellets in the rat. J. Pharmacol. Exp. Ther. 1986, 237, 126–130. [Google Scholar]
- Bisaga, A.; Nunes, E. Evaluation of Safety and Pharmacokinetics of Naltrexone Implant. Available online: https://grantome.com/grant/NIH/UG3-DA047720-01 (accessed on 15 November 2020).
- Crowley, P. Long-term drug treatment of patients with alcohol dependence. Aust. Prescr. 2015, 38, 41–43. [Google Scholar] [CrossRef] [Green Version]
- Bitri, S.T.; Puca, E.; Sotiri, E.; Thoma, E.; Puca, E. Liver Toxicity of Naltrexone. A Case Study and Review of Literature. 2018. Available online: http://medcraveonline.com (accessed on 23 December 2020).
- Yen, M.H.; Ko, H.C.; Tang, F.I.; Lu, R.B.; Hong, J.S. Study of hepatotoxicity of naltrexone in the treatment of alcoholism. Alcohol 2006, 38, 117–120. [Google Scholar] [CrossRef]
- Mitchell, M.C.; Memisoglu, A.; Silverman, B.L. Hepatic safety of injectable extended-release naltrexone in patients with chronic hepatitis C and HIV infection. J. Stud. Alcohol Drugs 2012, 73, 991–997. [Google Scholar] [CrossRef]
- Iovcheva, M.; Zlateva, S.; Asparuhova, M. Precipitated Withdrawal Reaction to Opiates in Cases of Improper Use of Naltrexone. 2007, Volume 13. Available online: http://www.journal-imab-bg.org (accessed on 23 December 2020).
- Boyce, S.H.; Armstrong, P.A.R.; Stevenson, J. Effect of innappropriate naltrexone use in a heroin misuser. Emerg. Med. J. 2003, 20, 381–382. [Google Scholar] [CrossRef] [Green Version]
- Colquhoun, R.; Tan, D.Y.K.; Hull, S. A comparison of oral and implant naltrexone outcomes at 12 months. J. Opioid Manag. 2005, 1, 249–256. [Google Scholar] [CrossRef] [Green Version]
- O’brien, C.P.; Greenstein, R.A.; Mintz, J.; Woody, G.E. Clinical experience with naltrexone. Am. J. Drug Alcohol Abus. 1975, 2, 365–377. [Google Scholar] [CrossRef]
- Minozzi, S.; Amato, L.; Vecchi, S.; Davoli, M.; Kirchmayer, U.; Verster, A. Oral naltrexone maintenance treatment for opioid dependence. In Cochrane Database of Systematic Reviews; John Wiley & Sons, Ltd.: Hoboken, NJ, USA, 2011. [Google Scholar]
- Caplehorn, J.R.M.; Dalton, M.S.Y.N.; Haldar, F.; Petrenas, A.M.; Nisbet, J.G. Methadone maintenance and addicts’ risk of fatal heroin overdose. Subst. Use Misuse 1996, 31, 177–196. [Google Scholar] [CrossRef]
- Comer, S.D.; Sullivan, M.A.; Hulse, G.K. Sustained-release naltrexone: Novel treatment for opioid dependence. Expert Opin. Investig. Drugs 2007, 16, 1285–1294. [Google Scholar] [CrossRef]
- Hulse, G.K.; Arnold-Reed, D.E.; O’Neil, G.; Chan, C.T.; Hansson, R.; O’Neil, P. Blood naltrexone and 6-β-naltrexol levels following naltrexone implant: Comparing two naltrexone implants. Addict. Biol. 2004, 9, 59–65. [Google Scholar] [CrossRef]
- Hulse, G.K.; Ngo, H.T.T.; Tait, R.J. Risk factors for craving and relapse in heroin users treated with oral or implant naltrexone. Biol. Psychiatry 2010, 68, 296–302. [Google Scholar] [CrossRef]
- Krupitsky, E.; Zvartau, E.; Blokhina, E.; Verbitskaya, E.; Wahlgren, V.; Tsoy-Podosenin, M.; Bushara, N.; Burakov, A.; Masalov, D.; Romanova, T.; et al. Anhedonia, depression, anxiety, and craving in opiate dependent patients stabilized on oral naltrexone or an extended release naltrexone implant. Am. J. Drug Alcohol Abus. 2016, 42, 614–620. [Google Scholar] [CrossRef] [Green Version]
- Ngo, H.T.T.; Tait, R.J.; Arnold-Reed, D.E.; Hulse, G.K. Mental health outcomes following naltrexone implant treatment for heroin-dependence. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2007, 31, 605–612. [Google Scholar] [CrossRef]
- Comer, S.D.; Sullivan, M.A.; Yu, E.; Rothenberg, J.L.; Kleber, H.D.; Kampman, K.; Dackis, C.; O’Brien, C.P. Injectable, sustained-release naltrexone for the treatment of opioid dependence: A randomized, placebo-controlled trial. Arch. Gen. Psychiatry 2006, 63, 210–218. [Google Scholar] [CrossRef]
System Involved | Associated Symptoms | Withdrawal or Use |
---|---|---|
Mesolimbic System | Intense cravings Depression Irritability | Withdrawal |
GI | Nausea Vomiting Diarrhea | Withdrawal |
Locus Coeruleus | Decreased respiration Decreased muscle tone Decreased blood pressure Drowsiness | Use |
Author (Year) | Groups Studied and Interventions | Results and Findings | Conclusions |
---|---|---|---|
Hulse G. et al. (2009) [33] | Phase IV Randomized, double-blinded, double placebo-controlled trial with a 6 month follow up period. Participants either received naltrexone implant with placebo oral medicine or a placebo implant with oral naltrexone. Main outcomes studied were blood naltrexone levels, return to heroin or other abused opioid use, opiate overdoses and other adverse events. | More participants in the oral vs. implant group had naltrexone levels below 2 ng/mL in their blood in the first (p = 0.001) and second (p = 0.01) months. More people in the oral group returned to heroin use at the 6 month mark (p = 0.003) and they had done so earlier than the implant group (median (SE), 115 (12.0) days vs. 158 (9.4) days). | Naltrexone implant reduces relapse to regular heroin use better than oral naltrexone and was not associated with major adverse events. |
Comer S. (2006) [64] | Phase IV randomized, double-blind, placebo-controlled, 8 week trial conducted at 2 medical centers. Participants were separated into placebo, or 192 mg or 384 mg dosage of depot naltrexone. All participants received relapse prevention therapy two times a week. Main outcomes measured were retention in treatment and percentage of opioid negative urine samples. | Retention in treatment was dose related with 39% in the placebo, 60% in the 192 mg, and 68% in the 382 mg group remaining at the end of the two-month mark. The mean number of days to dropout was lowest in the placebo group (27 days; 3.8 weeks), followed by the 192 mg of naltrexone group (36 days; 5.1 weeks), and the 384 mg of naltrexone group (48 days; 6.8 weeks). There was a significant difference in days to drop out between the placebo group and the 384 mg group (p < 0.001) and significant difference between the 384 mg group and the 192 mg groups (p = 0.046). | Long-lasting antagonist of the mu receptor is a feasible, efficacious, and tolerable treatment for OUD. |
Hulse G. et al. (2004) [60] | Phase IV Retrospective clinical record review of blood sample analysis results. Main outcomes measured were plasma levels of medication, retention rate, and time to drop out. | The mean (+SE) length of follow-up was 197.1 (+30.5) days (minimum length of follow-up was 70 days and the maximum 333 days). In patients who used the 1.7 g implant the blood levels of naltrexone were above 2 ng/mL for 90 days and remained above 1 ng/mL for 136 days on average. In the 3.4 g implant Blood naltrexone levels remained above 2 ng/mL for 188 days and remained about 1 ng/mL for 297 days on average. | Conclusions by this record review were that blood levels of naltrexone were markedly higher in this study than what has been reported in other studies. They also conclude that these implants offer significant improvements over earlier naltrexone implants previously reviewed. |
Colquhoun R. (2005) [55] | Phase IV cohort study following up patients that went through oral vs. implant naltrexone therapy for OUD. | The study showed a significant correlation with implant relapse and how long the participant though the implant was effective for (p < 0.05). There was also significant decrease in opiate relapse in the implant group when compared to the oral group (p < 0.05). | This study demonstrates the potential for implanted naltrexone to improve compliance rates, abstinence rates, and time in treatment when compared with oral naltrexone therapy. |
Hulse G. et al. (2010) [61] | Phase IV randomized, double-blinded, double dummy design where participants either received an active implant and placebo oral medication or active oral medication and placebo implant. Major outcomes measured were level of cravings, number of heroin uses per week, and any illicit opioid use. | The implant naltrexone participants were less likely to use any opioids when compared with the oral group. There was a significant correlation between naltrexone blood concentration and decreased cravings in the implant group (p = 0.0208). There was not a significant decrease in cravings with increased blood naltrexone levels in the oral group. There was less cravings seen in the implant group vs. the oral group but the difference between these two groups was not significant. | Naltrexone implants were associated with reduced heroin cravings and relapse when compared to oral naltrexone. Effective treatment range for the medication is 1–3 ng/mL in the blood. |
Ngo H. et al. (2006) [63] | Phase IV cohort study on heroin users treated with implanted naltrexone. Major outcomes measured were hospitalizations due to mental illness. | Patient’s risk for hospitalization due to mental illness was not affected by naltrexone use. In fact, there was a statistically significant (p < 0.05) decrease in hospitalization rates for mental illnesses after naltrexone therapy except for in mood disorders where there was no significant difference pre- and post-treatment. | Naltrexone implant was not associated with an increased risk for mental illness-related hospitalizations. In most cases it was associated with a decrease in hospitalizations due to mental illness excluding mood disorders. |
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Edinoff, A.N.; Nix, C.A.; Orellana, C.V.; StPierre, S.M.; Crane, E.A.; Bulloch, B.T.; Cornett, E.M.; Kozinn, R.L.; Kaye, A.M.; Murnane, K.S.; et al. Naltrexone Implant for Opioid Use Disorder. Neurol. Int. 2022, 14, 49-61. https://doi.org/10.3390/neurolint14010004
Edinoff AN, Nix CA, Orellana CV, StPierre SM, Crane EA, Bulloch BT, Cornett EM, Kozinn RL, Kaye AM, Murnane KS, et al. Naltrexone Implant for Opioid Use Disorder. Neurology International. 2022; 14(1):49-61. https://doi.org/10.3390/neurolint14010004
Chicago/Turabian StyleEdinoff, Amber N., Catherine A. Nix, Claudia V. Orellana, Samantha M. StPierre, Erin A. Crane, Blaine T. Bulloch, Elyse M. Cornett, Rachel L. Kozinn, Adam M. Kaye, Kevin S. Murnane, and et al. 2022. "Naltrexone Implant for Opioid Use Disorder" Neurology International 14, no. 1: 49-61. https://doi.org/10.3390/neurolint14010004