Login Register Cart 0
Generic placeholder image

Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Meta-Analysis

Model-based Meta-analysis to Compare Primary Efficacy-endpoint, Efficacy-time Course, Safety, and Tolerability of Opioids Used in the Management of Osteoarthritic Pain in Humans

Author(s): Suhaila Omar Alhaj-Suliman, Gary Milavetz and Aliasger Karimjee Salem*

Volume 21, Issue 5, 2020

Page: [390 - 399] Pages: 10

DOI: 10.2174/1389200221666200514130441

Price: $65

Abstract

Background: Despite recent therapeutic advances, osteoarthritis continues to be a challenging health problem, especially in the elderly population. Opioids, which are potent analgesics, have shown an extraordinary ability to reduce intense pain in many osteoarthritic clinical trials; however, there is an increased need for a study to integrate the reported outcomes and utilize them to achieve a better understanding. Herein, efficacy and safety aspects of opioids used to manage osteoarthritic pain were assessed and compared using a model-based meta-analysis (MBMA).

Methods: To perform the analysis, a comprehensive database consisting of pain relief compounds with information on summary-level of efficacy over time, adverse events and dropout rates was compiled from multiple sources. MBMA was conducted using a nonlinear mixed-effects modeling approach.

Results: The results of primary efficacy endpoint analysis indicated that the doses of oxycodone, oxymorphone, and tramadol required to produce 50% of the maximum effect were 47, 84, and 247 mg per day, respectively. Efficacytime course analysis showed that opioids had rapid time to efficacy onset, suggesting potentially powerful painrelieving effects. It was also found that gastrointestinal adverse events were the most opioid-associated and dosedependent adverse effects. In addition, the analysis revealed that opioids were well-tolerated at low to moderate doses.

Conclusion: This MBMA provides clinically meaningful insights into the efficacy and safety profiles of oxycodone, oxymorphone, and tramadol. Resultantly, the presented framework analysis can have an impact in the clinic on drug development where it can guide: the optimization of doses of opioids required to manage osteoarthritic pain; the making of precise key decisions for the positioning of new drugs, and; the design of more efficient trials.

Keywords: Opioids, osteoarthritis, model-based meta-analysis, efficacy-time course, safety, tolerability.

« Previous
Graphical Abstract

[1]
Xing, D.; Wang, B.; Liu, Q.; Ke, Y.; Xu, Y.; Li, Z.; Lin, J. Intra-articular Hyaluronic Acid in Treating Knee Osteoarthritis: a PRISMA-Compliant Systematic Review of Overlapping Meta-analysis. Sci. Rep., 2016, 6, 32790.
[http://dx.doi.org/10.1038/srep32790] [PMID: 27616273]
[2]
Sinusas, K. Osteoarthritis: diagnosis and treatment. Am. Fam. Physician, 2012, 85(1), 49-56.
[PMID: 22230308]
[3]
Zhang, W.; Moskowitz, R.W.; Nuki, G.; Abramson, S.; Altman, R.D.; Arden, N.; Bierma-Zeinstra, S.; Brandt, K.D.; Croft, P.; Doherty, M.; Dougados, M.; Hochberg, M.; Hunter, D.J.; Kwoh, K.; Lohmander, L.S.; Tugwell, P. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage, 2008, 16(2), 137-162.
[http://dx.doi.org/10.1016/j.joca.2007.12.013] [PMID: 18279766]
[4]
Neogi, T. The epidemiology and impact of pain in osteoarthritis. Osteoarthritis Cartilage, 2013, 21(9), 1145-1153.
[http://dx.doi.org/10.1016/j.joca.2013.03.018] [PMID: 23973124]
[5]
Ma, V.Y.; Chan, L.; Carruthers, K.J. Incidence, prevalence, costs, and impact on disability of common conditions requiring rehabilitation in the United States: stroke, spinal cord injury, traumatic brain injury, multiple sclerosis, osteoarthritis, rheumatoid arthritis, limb loss, and back pain. Arch Phys Med Rehabil, 2014, 95(5), 986-995. e1
[http://dx.doi.org/10.1016/j.apmr.2013.10.032]
[6]
Conn, P.M.; Benjamin, S.A.; Finch, C.E.; Guerin, J.C.; Nelson, J.F.; Olshansky, S.J.; Roth, G.; Smith, R.G. Handbook of Models for Human Aging; Elsevier Science, 2011.
[7]
Ungprasert, P.; Kittanamongkolchai, W.; Price, C.; Ratanapo, S.; Leeaphorn, N.; Chongnarungsin, D.; Cheungpasitporn, W. Safest non-steroid anti-inflam drug? Am. J. Med., 2012, 3, 115-123.
[8]
Pirmohamed, M.; James, S.; Meakin, S.; Green, C.; Scott, A.K.; Walley, T.J.; Farrar, K.; Park, B.K.; Breckenridge, A.M. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ, 2004, 329(7456), 15-19.
[http://dx.doi.org/10.1136/bmj.329.7456.15] [PMID: 15231615]
[9]
Matsumoto, A.K.; Babul, N.; Ahdieh, H. Oxymorphone extended-release tablets relieve moderate to severe pain and improve physical function in osteoarthritis: results of a randomized, double-blind, placebo- and active-controlled phase III trial. Pain Med., 2005, 6(5), 357-366.
[http://dx.doi.org/10.1111/j.1526-4637.2005.00057.x] [PMID: 16266356]
[10]
Guideline for the management of pain in osteoarthritis, rheumatoid arthritis, and juvenile chronic arthritis, 2002.
[11]
https://www.arthritis.org/about-arthritis/types/osteoarthritis/treatment.php
[12]
Dowell, D.; Haegerich, T.M.; Chou, R. CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016. MMWR Recomm. Rep., 2016, 65(1), 1-49.
[http://dx.doi.org/10.15585/mmwr.rr6501e1] [PMID: 26987082]
[13]
Manchikanti, L.; Helm, S., II; Fellows, B.; Janata, J.W.; Pampati, V.; Grider, J.S.; Boswell, M.V. Opioid epidemic in the United States. Pain Physician, 2012, 15(3)(Suppl.), ES9-ES38.
[PMID: 22786464]
[14]
Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence; Geneva, 2009.
[15]
Mercier, F.; Claret, L.; Prins, K.; Bruno, R. A Model-Based Meta-analysis to Compare Efficacy and Tolerability of Tramadol and Tapentadol for the Treatment of Chronic Non-Malignant Pain. Pain Ther., 2014, 3(1), 31-44.
[http://dx.doi.org/10.1007/s40122-014-0023-5] [PMID: 25135386]
[16]
Haidich, A.B. Meta-analysis in medical research. Hippokratia, 2010, 14(Suppl. 1), 29-37.
[PMID: 21487488]
[17]
Mould, D.R. Model-based meta-analysis: an important tool for making quantitative decisions during drug development. Clin. Pharmacol. Ther., 2012, 92(3), 283-286.
[http://dx.doi.org/10.1038/clpt.2012.122] [PMID: 22910485]
[18]
McGrory, B.J.; Harris, W.H. Can the western Ontario and McMaster Universities (WOMAC) osteoarthritis index be used to evaluate different hip joints in the same patient? J. Arthroplasty, 1996, 11(7), 841-844.
[http://dx.doi.org/10.1016/S0883-5403(96)80184-7] [PMID: 8934324]
[19]
Ting, N. Dose Finding in Drug Development; Springer New York, 2006.
[http://dx.doi.org/10.1007/0-387-33706-7]
[20]
Markenson, J.A.; Croft, J.; Zhang, P.G.; Richards, P. Treatment of persistent pain associated with osteoarthritis with controlled-release oxycodone tablets in a randomized controlled clinical trial. Clin. J. Pain, 2005, 21(6), 524-535.
[http://dx.doi.org/10.1097/01.ajp.0000146215.86038.38] [PMID: 16215338]
[21]
Hale, M.; Tudor, I.C.; Khanna, S.; Thipphawong, J. Efficacy and tolerability of once-daily OROS hydromorphone and twice-daily extended-release oxycodone in patients with chronic, moderate to severe osteoarthritis pain: results of a 6-week, randomized, open-label, noninferiority analysis. Clin. Ther., 2007, 29(5), 874-888.
[http://dx.doi.org/10.1016/j.clinthera.2007.05.016] [PMID: 17697906]
[22]
Afilalo, M.; Etropolski, M.S.; Kuperwasser, B.; Kelly, K.; Okamoto, A.; Van Hove, I.; Steup, A.; Lange, B.; Rauschkolb, C.; Haeussler, J. Efficacy and safety of Tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee: a randomized, double-blind, placebo- and active-controlled phase III study. Clin. Drug Investig., 2010, 30(8), 489-505.
[http://dx.doi.org/10.2165/11533440-000000000-00000] [PMID: 20586515]
[23]
Spierings, E.L.; Fidelholtz, J.; Wolfram, G.; Smith, M.D.; Brown, M.T.; West, C.R. A phase III placebo- and oxycodone-controlled study of tanezumab in adults with osteoarthritis pain of the hip or knee. Pain, 2013, 154(9), 1603-1612.
[http://dx.doi.org/10.1016/j.pain.2013.04.035] [PMID: 23707270]
[24]
Kivitz, A.; Ma, C.; Ahdieh, H.; Galer, B.S. A 2-week, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase III trial comparing the efficacy of oxymorphone extended release and placebo in adults with pain associated with osteoarthritis of the hip or knee. Clin. Ther., 2006, 28(3), 352-364.
[http://dx.doi.org/10.1016/j.clinthera.2006.03.008] [PMID: 16750450]
[25]
Silverfield, J.C.; Kamin, M.; Wu, S.C.; Rosenthal, N. Tramadol/acetaminophen combination tablets for the treatment of osteoarthritis flare pain: a multicenter, outpatient, randomized, double-blind, placebo-controlled, parallel-group, add-on study. Clin. Ther., 2002, 24(2), 282-297.
[http://dx.doi.org/10.1016/S0149-2918(02)85024-X] [PMID: 11911558]
[26]
Emkey, R.; Rosenthal, N.; Wu, S.C.; Jordan, D.; Kamin, M. Efficacy and safety of tramadol/acetaminophen tablets (Ultracet) as add-on therapy for osteoarthritis pain in subjects receiving a COX-2 nonsteroidal antiinflammatory drug: a multicenter, randomized, double-blind, placebo-controlled trial. J. Rheumatol., 2004, 31(1), 150-156.
[PMID: 14705234]
[27]
Babul, N.; Noveck, R.; Chipman, H.; Roth, S.H.; Gana, T.; Albert, K. Efficacy and safety of extended-release, once-daily tramadol in chronic pain: a randomized 12-week clinical trial in osteoarthritis of the knee. J. Pain Symptom Manage., 2004, 28(1), 59-71.
[http://dx.doi.org/10.1016/j.jpainsymman.2003.11.006] [PMID: 15223085]
[28]
Burch, F.; Fishman, R.; Messina, N.; Corser, B.; Radulescu, F.; Sarbu, A.; Craciun-Nicodin, M.M.; Chiriac, R.; Beaulieu, A.; Rodrigues, J.; Beignot-Devalmont, P.; Duplan, A.; Robertson, S.; Fortier, L.; Bouchard, S. A comparison of the analgesic efficacy of Tramadol Contramid OAD versus placebo in patients with pain due to osteoarthritis. J. Pain Symptom Manage., 2007, 34(3), 328-338.
[http://dx.doi.org/10.1016/j.jpainsymman.2006.11.017] [PMID: 17583466]
[29]
Fishman, R.L.; Kistler, C.J.; Ellerbusch, M.T.; Aparicio, R.T.; Swami, S.S.; Shirley, M.E.; Jain, A.K.; Fortier, L.; Robertson, S.; Bouchard, S. Efficacy and safety of 12 weeks of osteoarthritic pain therapy with once-daily tramadol (Tramadol Contramid OAD). J. Opioid. Manag., 2007, 3(5), 273-280.
[http://dx.doi.org/10.5055/jom.2007.0015] [PMID: 18181382]
[30]
Thorne, C.; Beaulieu, A.D.; Callaghan, D.J.; O’Mahony, W.F.; Bartlett, J.M.; Knight, R.; Kraag, G.R.; Akhras, R.; Piraino, P.S.; Eisenhoffer, J.; Harsanyi, Z.; Darke, A.C. A randomized, double-blind, crossover comparison of the efficacy and safety of oral controlled-release tramadol and placebo in patients with painful osteoarthritis. Pain Res. Manag., 2008, 13(2), 93-102.
[http://dx.doi.org/10.1155/2008/165421] [PMID: 18443671]
[31]
Beaulieu, A.D.; Peloso, P.M.; Haraoui, B.; Bensen, W.; Thomson, G.; Wade, J.; Quigley, P.; Eisenhoffer, J.; Harsanyi, Z.; Darke, A.C. Once-daily, controlled-release tramadol and sustained-release diclofenac relieve chronic pain due to osteoarthritis: a randomized controlled trial. Pain Res. Manag., 2008, 13(2), 103-110.
[http://dx.doi.org/10.1155/2008/903784] [PMID: 18443672]
[32]
DeLemos, B.P.; Xiang, J.; Benson, C.; Gana, T.J.; Pascual, M.L.; Rosanna, R.; Fleming, B. Tramadol hydrochloride extended-release once-daily in the treatment of osteoarthritis of the knee and/or hip: a double-blind, randomized, dose-ranging trial. Am. J. Ther., 2011, 18(3), 216-226.
[http://dx.doi.org/10.1097/MJT.0b013e3181cec307] [PMID: 20215961]
[33]
Gana, T.J.; Pascual, M.L.; Fleming, R.R.; Schein, J.R.; Janagap, C.C.; Xiang, J.; Vorsanger, G.J.; Study, G. Extended-release tramadol in the treatment of osteoarthritis: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Curr. Med. Res. Opin., 2006, 22(7), 1391-1401.
[http://dx.doi.org/10.1185/030079906X115595] [PMID: 16834838]
[34]
https://www.bcbsks.com/customerservice/Providers/MedicalPolicies/policies/policies/OpioidsExtendedRelease_2017-07-14.pdf
[35]
Caldwell, J.R.; Hale, M.E.; Boyd, R.E.; Hague, J.M.; Iwan, T.; Shi, M.; Lacouture, P.G. Treatment of osteoarthritis pain with controlled release oxycodone or fixed combination oxycodone plus acetaminophen added to nonsteroidal antiinflammatory drugs: a double blind, randomized, multicenter, placebo controlled trial. J. Rheumatol., 1999, 26(4), 862-869.
[PMID: 10229408]
[36]
Roth, S.H.; Fleischmann, R.M.; Burch, F.X.; Dietz, F.; Bockow, B.; Rapoport, R.J.; Rutstein, J.; Lacouture, P.G. Around-the-clock, controlled-release oxycodone therapy for osteoarthritis-related pain: placebo-controlled trial and long-term evaluation. Arch. Intern. Med., 2000, 160(6), 853-860.
[http://dx.doi.org/10.1001/archinte.160.6.853] [PMID: 10737286]
[37]
Chindalore, V.L.; Craven, R.A.; Yu, K.P.; Butera, P.G.; Burns, L.H.; Friedmann, N. Adding ultralow-dose naltrexone to oxycodone enhances and prolongs analgesia: a randomized, controlled trial of Oxytrex. J. Pain, 2005, 6(6), 392-399.
[http://dx.doi.org/10.1016/j.jpain.2005.01.356] [PMID: 15943961]
[38]
Hale, M.; Upmalis, D.; Okamoto, A.; Lange, C.; Rauschkolb, C. Tolerability of tapentadol immediate release in patients with lower back pain or osteoarthritis of the hip or knee over 90 days: a randomized, double-blind study. Curr. Med. Res. Opin., 2009, 25(5), 1095-1104.
[http://dx.doi.org/10.1185/03007990902816970] [PMID: 19301989]
[39]
Hartrick, C.; Van Hove, I.; Stegmann, J.U.; Oh, C.; Upmalis, D. Efficacy and tolerability of tapentadol immediate release and oxycodone HCl immediate release in patients awaiting primary joint replacement surgery for end-stage joint disease: a 10-day, phase III, randomized, double-blind, active- and placebo-controlled study. Clin. Ther., 2009, 31(2), 260-271.
[http://dx.doi.org/10.1016/j.clinthera.2009.02.009] [PMID: 19302899]
[40]
McIlwain, H.; Ahdieh, H. Safety, tolerability, and effectiveness of oxymorphone extended release for moderate to severe osteoarthritis pain: a one-year study. Am. J. Ther., 2005, 12(2), 106-112.
[http://dx.doi.org/10.1097/01.mjt.0000139442.65914.f9] [PMID: 15767827]
[41]
Malonne, H.; Coffiner, M.; Sonet, B.; Sereno, A.; Vanderbist, F. Efficacy and tolerability of sustained-release tramadol in the treatment of symptomatic osteoarthritis of the hip or knee: a multicenter, randomized, double-blind, placebo-controlled study. Clin. Ther., 2004, 26(11), 1774-1782.
[http://dx.doi.org/10.1016/j.clinthera.2004.11.005] [PMID: 15639689]
[42]
Choi, C.B.; Song, J.S.; Kang, Y.M.; Suh, C.H.; Lee, J.; Choe, J.Y.; Lee, C.K.; Shim, S.C.; Chung, W.T.; Song, G.G.; Kim, H.A.; Ji, J.D.; Nam, E.J.; Park, S.H.; Hong, Y.H.; Sheen, D.H.; Lim, M.K.; Seo, Y.I.; Sung, Y.K.; Kim, T.H.; Lee, J.T.; Bae, S.C. A 2-week, multicenter, randomized, double-blind, double-dummy, add-on study of the effects of titration on tolerability of tramadol/acetaminophen combination tablet in Korean adults with knee osteoarthritis pain. Clin. Ther., 2007, 29(7), 1381-1389.
[http://dx.doi.org/10.1016/j.clinthera.2007.07.015] [PMID: 17825689]
[43]
Corsinovi, L.; Martinelli, E.; Fonte, G.; Astengo, M.; Sona, A.; Gatti, A.; Massaia, M.; Bo, M.; Zanocchi, M.; Michelis, G.; Isaia, G.; Molaschi, M. Efficacy of oxycodone/acetaminophen and codeine/acetaminophen vs. conventional therapy in elderly women with persistent, moderate to severe osteoarthritis-related pain. Arch. Gerontol. Geriatr., 2009, 49(3), 378-382.
[http://dx.doi.org/10.1016/j.archger.2008.12.003] [PMID: 19150139]
[44]
Zautra, A.J.; Smith, B.W. Impact of controlled-release oxycodone on efficacy beliefs and coping efforts among osteoarthritis patients with moderate to severe pain. Clin. J. Pain, 2005, 21(6), 471-477.
[http://dx.doi.org/10.1097/01.ajp.0000139910.97211.37] [PMID: 16215331]
[45]
Teng, Z.; Gupta, N.; Hua, Z.; Liu, G.; Samnotra, V.; Venkatakrishnan, K.; Labotka, R. Model-based meta-analysis for multiple myeloma: A quantitative drug-independent framework for efficient decisions in oncology drug development. Clin. Transl. Sci., 2018, 11(2), 218-225.
[PMID: 29168990]
[46]
https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/022272lbl.pdf
[47]
Bell, T.J.; Panchal, S.J.; Miaskowski, C.; Bolge, S.C.; Milanova, T.; Williamson, R. The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European Patient Survey (PROBE 1). Pain Med., 2009, 10(1), 35-42.
[http://dx.doi.org/10.1111/j.1526-4637.2008.00495.x] [PMID: 18721170]

Rights & Permissions Print Cite
Article Metrics
64
© 2024 Bentham Science Publishers | Privacy Policy