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Buprenorphine Not a Silver Bullet but an Opioid of Choice for Chronic Pain Mellar P

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Buprenorphine Not a Silver Bullet but an Opioid of Choice for Chronic Pain Mellar P JOM_BUPE_Davis_Editorial 8/5/2021 10:29 AM Page 11 DOI:10.5055/jom.2021.0619 EDITORIAL Buprenorphine not a silver bullet but an opioid of choice for chronic pain Mellar P. Davis, MD, FCCP, FAAHPM; Jeffrey Fudin, PharmD, FACCP, FASHP, FFSMB I want to thank Dr. Potru for his thoughtful letter Norbuprenorphine is responsible for the respiratory 12-14 and would like to respond in kind. I agree that depression associated with buprenorphine. chronic pain should be treated with a multi-discipli - Buprenorphine does not but norbuprenorphine does nary approach and not treated solely with opioids as activate beta-arrestin and beta-arrestin activation 1 a single modality. I also agree that opioid therapy appears to be responsible, at least in part, for constipa - should be a trial and only considered when other tion and respiratory depression observed with non-opioid medications and modalities have failed buprenorphine. Blocking norbuprenorphine produc - 2,3 to improve patient function. We also agree that tion as a result of blocking CYP3A4 may increase 15,16 universal precautions should be used for all opioids buprenorphine utility and safety. The affinity of used to treat chronic noncancer pain. We also agree buprenorphine and metabolites for various receptors is that the long-term results of opioid therapy is not outlined on Table 1. What is evident from this table is 4,5 established. There are a large number of patients that buprenorphine is not a nociceptin agonist and that who discontinue opioid therapy due to side effects. only buprenorphine-3-glucuronide of the glucuronides Iatrogenic addiction is a risk as well as other long- has MOR activity. 6 term and even short-term adverse effects. However, We can summarize buprenorphine pharmacody - there are a subset of patients who do benefit from namics in the following way: 7 opioid therapy in the long-term. Buprenorphine was originally developed by Alan • Norbuprenorphine has mu activity and is a Cowan, PhD as a safer (not absolutely safe) anal - potent full agonist gesic and is a schedule III opioid as a result rather than schedule II. Buprenorphine was originally • Buprenorphine is a partial agonist at mu-1 developed as an analgesic and it was only later that and a kappa antagonist it was used as an opioid maintenance therapy. Heit and Covington, published a letter addressing the • Buprenorphine-3-glucuronide has partial issue to the DEA regarding the use of buprenor - mu and delta, but not kappa activity phine-naloxone for analgesia. The response was though buprenorphine-naloxone is licensed for opi - • Norbuprenorphine-3-glucuronide has kappa oid maintenance therapy, its use is not limited to activity and nociception, but no mu or delta maintenance therapy and it can be used as an anal - activity 8 gesic. Dr. Potru mentioned that buprenorphine is metabo - It is generally accepted, but not carefully studied lized by a the cytochrome CYP3A4 but the rate limiting that partial agonists cause less constipation; presum - metabolism is through the glucuronidases UGT1A1, ably, only the parent compound, and presumably 9-11 UGT1A3 and UGT2B7. Norbuprenorphine is an the 3-glucuronide metabolite (passage back into gut active metabolite as a “full” agonist at MOR but is from circulation) are present in the gut, but not nor - excluded from the CNS by P-glycoprotein. Its analgesic buprenorphine. Standard buprenorphine sublingual potential is ¼-1/50th that of buprenorphine. doses of 8mg will produce peak concentrations of n Journal of Opioid Management 17:7 Special Issue 11 Buprenorphine: Clinical and Public Policy Implications JOM_BUPE_Davis_Editorial 8/5/2021 10:29 AM Page 12 41 “Recommendation 4B: Encourage CMS and Table1. Buprenorphine and metabolite affinity (IC50) private payers to provide coverage and reimbursement for buprenorphine treat - MOP DOP KOP NOP Opioid ng/ml ng/ml ng/ml ng/ml ment, both for OUD and for chronic pain. Encourage primary use of buprenorphine Buprenorphine 0.00013 15 0.00098 11,675 rather than use only after failure of standard me you agonist opioids such as hydro - Norbuprenorphine 0.00084 607 0.0006 16,812 codone or fentanyl, if clinically indicated.” Buprenorphine-3- “Recommendation for CV: Encourage clini - 0.0023 126 NB 16,812 Glucuronide cal trials using buprenorphine for chronic pain to better understand indications, usage Norbuprenorphine- NB NB 140,000 8,406 3-Glucuronide and dosage.” buprenorphine of 10-12 nanograms/ml(ng/ml), The reasons for such a recommendation are norbuprenorphine 1 ng/ml, buprenorphine-3-glu - described on page 25 of the committee report and curonide 3ng/ml and norbuprenorphine-3-glu - are quoted here: “Buprenorphine, an opioid med - 17 curonide of 3.5ng/ml. ication that the FDA has approved for clinical use, is Another unique pharmacodynamic mechanism to a partial agonist at the mu opioid receptor and buprenorphine which is shared with nalbuphine, therefore has a reduced potential for respiratory butorphanol and levorphanol involves interactions depression; it is thus safer than full agonists such as with the exon 11 6-transmembrane MOR receptors. morphine, hydrocodone, and oxycodone. Bupren - Analgesics which are partial agonists at this receptor orphine also acts as an antagonist at the kappa 18-24 have a ceiling on respiratory depression. receptor, an effect shown in experimental studies to Buprenorphine is as effective in managing acute reduce anxiety, depression, and the unpleasantness pain at all timeframes (from less than 1 hour to 48 of opioid withdrawal. Buprenorphine is widely 25 hours) as is morphine. Pain relief is no different used and encouraged for treating patients with between transdermal buprenorphine and sublingual OUD and is approved for the treatment of pain. In 26 buprenorphine. Transdermal fentanyl has a greater some states, there is a significant challenge, howev - risk for respiratory depression per does-concentration er, for prescribing clinicians to get authorization for 27-37 ratio than fentanyl. Buprenorphine is a better anal - using buprenorphine for chronic pain management gesic and is less constipating than morphine though (Section 2.2: Medication, Gap 4 and Recom - 27,28,38 buprenorphine may have greater nausea. The mendations).” analgesia of buprenorphine is greater in patients with In regard to other comments, I would agree that chronic pain without an opioid use disorder (OUD) naltrexone is a reasonable and perhaps safer choice than those with pain and an OUD. This may reflect the for maintenance therapy than buprenorphine. I 39 psychological milieu of addiction and not the opioid. would agree that the addition of any benzodi - The anesthesiology literature contains reviews which azepine to any opioid is a hazardous practice. 40 are favorable towards buprenorphine as an analgesic. Buprenorphine can be abused, and universal pre - The United States Department of Health And cautions should be used if prescribed for pain. Humans Services monograph entitled “Pain Manage - ment Best Practices Inter Agency Task Force Report: Updates, Gaps, Inconsistencies and Recommen da- Mellar P. Davis, MD, FCCP, FAAHPM, Geisinger Medical tions” (May 2019) ( https://www.hhs. gov/ash/advisory Center, Danville Pennsylvania. committees/pain/reports/index.html; accessed 2/24/ 2021) has the following recommendations (page 29): Jeffrey Fudin, PharmD, FACCP, FASHP, FFSMB, Adjunct Associate Professor, Albany College of Pharmacy and Health “Recommendation 4A: Buprenorphine treat - Sciences, Albany New York; Adjunct Associate Professor, ment for chronic pain available for specific Western New England University College of Pharmacy, Springfield Massachusetts; President, Remitigate Thera - groups of patients and include buprenorphine peutics, Delmar New York. in third-party payer and hospital formularies.” n 12 Journal of Opioid Management 17:7 Special Issue Buprenorphine: Clinical and Public Policy Implications JOM_BUPE_Davis_Editorial 8/5/2021 10:29 AM Page 13 REFERENCES 16. 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Dowell D, Haegerich TM: Using the CDC Guideline and Analgesic. Anesth Analg . 2019; 128(2): 365-373. Tools for Opioid Prescribing in Patients with Chronic Pain. Am Fam Physician . 2016; 93(12): 970-972. 19. Lu Z, Xu J, Xu M, et al.: Truncated mu-Opioid Receptors With 6 Transmembrane Domains Are Essential for Opioid 4. Iacobellis A, Seripa D, Palmieri O, et al.: Efficacy and Safety of Analgesia. Anesth Analg . 2018; 126(3): 1050-1057. Long-Term Administration of Tapentadol in Relieving Chronic Pancreatitis Pain. Pain Med . 2017; 18(4): 815-817. 20. Grinnell SG, Ansonoff M, Marrone GF, et al.: Mediation of buprenorphine analgesia by a combination of traditional and 5. Howard RF, Radic T, Sohns M, et al.: Tapentadol Prolonged truncated mu opioid receptor splice variants. Synapse . 2016; Release for Long-Term Treatment of Pain in Children. J Pain 70(10): 395-407. Res . 2020; 13: 3157-3170. 21. Marrone GF, Majumdar S, Pasternak GW: Radioligand 6. 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