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Side Effects of Central Analgesic Drugs

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Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays

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Abstract

Strong opioid analgesics, such as morphine, are the most widely used, centrally acting class of analgesics that are available in the clinic for the treatment of moderate to severe acute nociceptive pain and chronic cancer-related pain. However, strong opioid analgesics also evoke a broad array of side effects including sedation, respiratory depression, nausea and vomiting, pruritus, analgesic tolerance, constipation, and addiction/abuse liability, to name but a few. Due to the “opioid crisis” particularly in the United States, use of strong opioids to alleviate chronic noncancer pain is controversial due to unintentional respiratory depression and opioid misuse/abuse. Additionally, for patients with chronic cancer-related pain, constipation is a major cause of non-compliance. Hence, there is a large unmet medical need for novel, highly effective, safe, and well-tolerated strong opioid analgesics. In this chapter, we describe protocols currently used to evaluate important opioid-related centrally mediated adverse effects. These include protocols for assessing respiratory depression, sedation, constipation, physical dependence, and abuse liability using rodent and non-human primate models.

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References and Further Reading

  • Avsaroglu H, Van Der Sar AS, Van Lith HA, Van Zutphen LF, Hellebrekers LJ (2007) Differences in response to anaesthetics and analgesics between inbred rat strains. Lab Anim 41:337–344

    Article  CAS  PubMed  Google Scholar 

  • Basiri F, Rad A, Mahdian D, Molavi M, Amin B (2019) Effects of glucosamine against morphine-induced antinociceptive tolerance and dependence in mice. J Biomed Sci 26:21

    Article  PubMed  PubMed Central  Google Scholar 

  • Blackwood CA, Mccoy MT, Ladenheim B, Cadet JL (2020) Escalated oxycodone self-administration and punishment: differential expression of opioid receptors and immediate early genes in the rat dorsal striatum and prefrontal cortex. Front Neurosci 13

    Google Scholar 

  • Bohn LM, Gainetdinov RR, Sotnikova TD, Medvedev IO, Lefkowitz RJ, Dykstra LA, Caron MG (2003) Enhancing rewarding properties of morphine, but not cocaine, in beta(arrestin)-2 knock-out mice. J Neurosci 23:10265–10273

    Google Scholar 

  • Bosse GD, Cadeddu R, Floris G, Farero RD, Vigato E, Lee SJ, Zhang T, Gaikwad NW, Keefe KA, Phillips PEM, Bortolato M, Peterson RT (2021) The 5α-reductase inhibitor finasteride reduces opioid self-administration in animal models of opioid use disorder. J Clin Investig 131:e143990

    Article  CAS  PubMed Central  Google Scholar 

  • Browning KN, Travagli RA (2014) Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions. Compr Physiol 4:1339–1368

    Article  PubMed  PubMed Central  Google Scholar 

  • Browning KN, Travagli RA (2019) Central control of gastrointestinal motility. Curr Opin Endocrinol Diabetes Obes 26:11–16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Choe CH, Smith FL (2000) Sedative tolerance accompanies tolerance to the analgesic effects of fentanyl in infant rats. Pediatr Res 47:727–735

    Article  CAS  PubMed  Google Scholar 

  • Cordery SF, Taverner A, Ridzwan IE, Guy RH, Delgado-Charro MB, Husbands SM, Bailey CP (2014) A non-rewarding, non-aversive buprenorphine/naltrexone combination attenuates drug-primed reinstatement to cocaine and morphine in rats in a conditioned place preference paradigm. Addict Biol 19:575–586

    Article  CAS  PubMed  Google Scholar 

  • Coussens NP, Sittampalam GS, Jonson SG, Hall MD, Gorby HE, Tamiz AP, Mcmanus OB, Felder CC, Rasmussen K (2019) The opioid crisis and the future of addiction and pain therapeutics. J Pharmacol Exp Ther 371:396–408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Criée CP, Sorichter S, Smith HJ, Kardos P, Merget R, Heise D, Berdel D, Köhler D, Magnussen H, Marek W, Mitfessel H, Rasche K, Rolke M, Worth H, Jörres RA (2011) Body plethysmography – its principles and clinical use. Respir Med 105:959–971

    Article  PubMed  Google Scholar 

  • Dallas ML, Peers C, Golder FJ, Baby S, Gruber R, Macintyre DE (2015) GAL-021 and GAL-160 are efficacious in rat models of obstructive and central sleep apnea and inhibit BKCa in isolated rat carotid body glomus cells. Adv Exp Med Biol 860:361–370

    Article  CAS  PubMed  Google Scholar 

  • Darcq E, Kieffer BL (2018) Opioid receptors: drivers to addiction? Nat Rev Neurosci 19:499–514

    Article  CAS  PubMed  Google Scholar 

  • Decker MJ, Conrad KP, Strohl KP (1989) Noninvasive oximetry in the rat. Biomed Instrum Technol 23:222–228

    CAS  PubMed  Google Scholar 

  • Di Stefano G, Di Lionardo A, Di Pietro G, Cruccu G, Truini A (2021) Pharmacotherapeutic options for managing neuropathic pain: a systematic review and meta-analysis. Pain Res Manag 2021:6656863

    Article  PubMed  PubMed Central  Google Scholar 

  • Ding H, Ko MC (2021) Translational value of non-human primates in opioid research. Exp Neurol 338:113602

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ding H, Czoty PW, Kiguchi N, Cami-Kobeci G, Sukhtankar DD, Nader MA, Husbands SM, Ko M-C (2016) A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates. Proc Natl Acad Sci 113:E5511–E5518

    CAS  PubMed  PubMed Central  Google Scholar 

  • Enhanced rewarding properties of morphine, but not cocaine, in beta(arrestin)-2 knock-out mice. J Neurosci 23:10265–10273

    Google Scholar 

  • Fujita W, Gomes I, Dove LS, Prohaska D, Mcintyre G, Devi LA (2014) Molecular characterization of eluxadoline as a potential ligand targeting mu-delta opioid receptor heteromers. Biochem Pharmacol 92:448–456

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gallantine EL, Meert TF (2005) A comparison of the antinociceptive and adverse effects of the mu-opioid agonist morphine and the delta-opioid agonist SNC80. Basic Clin Pharmacol Toxicol 97:39–51

    Article  CAS  PubMed  Google Scholar 

  • Green TA, Bardo MT (2020) Opposite regulation of conditioned place preference and intravenous drug self-administration in rodent models: motivational and non-motivational examples. Neurosci Biobehav Rev 116:89–98

    Article  PubMed  PubMed Central  Google Scholar 

  • He L, Gooding SW, Lewis E, Felth LC, Gaur A, Whistler JL (2021) Pharmacological and genetic manipulations at the μ-opioid receptor reveal arrestin-3 engagement limits analgesic tolerance and does not exacerbate respiratory depression in mice. Neuropsychopharmacology 46:2241–2249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang Y-H, Wu Y-W, Chuang J-Y, Chang Y-C, Chang H-F, Tao P-L, Loh HH, Yeh S-H (2020) Morphine produces potent antinociception, sedation, and hypothermia in humanized mice expressing human mu-opioid receptor splice variants. Pain 161:1177–1190

    Article  CAS  PubMed  Google Scholar 

  • Imam MZ, Kuo A, Ghassabian S, Smith MT (2018) Progress in understanding mechanisms of opioid-induced gastrointestinal adverse effects and respiratory depression. Neuropharmacology 131:238–255

    Article  CAS  PubMed  Google Scholar 

  • Imam MZ, Kuo A, Ghassabian S, Cai Y, Qin Y, Li T, Smith MT (2020a) Intracerebroventricular administration of CYX-6, a potent μ-opioid receptor agonist, a δ- and κ-opioid receptor antagonist and a biased ligand at μ, δ & κ-opioid receptors, evokes antinociception with minimal constipation and respiratory depression in rats in contrast to morphine. Eur J Pharmacol 172918

    Google Scholar 

  • Imam MZ, Kuo A, Smith MT (2020b) Countering opioid-induced respiratory depression by non-opioids that are respiratory stimulants. F1000Research 9:F1000 Faculty Rev-91

    Article  PubMed  PubMed Central  Google Scholar 

  • Ingram SL, Fossum EN, Morgan MM (2007) Behavioral and electrophysiological evidence for opioid tolerance in adolescent rats. Neuropsychopharmacology 32:600–606

    Article  CAS  PubMed  Google Scholar 

  • Jerussi TP, Capacchione JF, Benvenga MJ (1987) Reversal of opioid-induced muscular rigidity in rats: evidence for alpha-2 adrenergic involvement. Pharmacol Biochem Behav 28:283–289

    Article  CAS  PubMed  Google Scholar 

  • Katz JL (1986) Effects of clonidine and morphine on opioid withdrawal in rhesus monkeys. Psychopharmacology 88:392–397

    Article  CAS  PubMed  Google Scholar 

  • Kishioka S, Paronis CA, Woods JH (2000) Acute dependence on, but not tolerance to, heroin and morphine as measured by respiratory effects in rhesus monkeys. Eur J Pharmacol 398:121–130

    Article  CAS  PubMed  Google Scholar 

  • Kissin I, Brown PT, Robinson CA, Bradley EL Jr (1991) Acute tolerance to the hypnotic effect of morphine in rats. Anesth Analg 73:619–621

    CAS  PubMed  Google Scholar 

  • Kliewer A, Gillis A, Hill R, Schmiedel F, Bailey C, Kelly E, Henderson G, Christie MJ, Schulz S (2020) Morphine-induced respiratory depression is independent of β-arrestin 2 signalling. Br J Pharmacol 177:2923–2931

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ko MCH, Divin MF, Lee H, Woods JH, Traynor JR (2006) Differential in vivo potencies of naltrexone and 6β-naltrexol in the monkey. J Pharmacol Exp Ther 316:772–779

    Article  CAS  PubMed  Google Scholar 

  • Kosten TR, George TP (2002) The neurobiology of opioid dependence: implications for treatment. Sci Pract Perspect 1:13–20

    Article  PubMed  PubMed Central  Google Scholar 

  • Kuhn BN, Kalivas PW, Bobadilla A-C (2019) Understanding addiction using animal models. Front Behav Neurosci 13:262–262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kuo A, Wyse BD, Meutermans W, Smith MT (2015) In vivo profiling of seven common opioids for antinociception, constipation and respiratory depression: no two opioids have the same profile. Br J Pharmacol 172:532–548

    Article  CAS  PubMed  Google Scholar 

  • Lowery JJ, Raymond TJ, Giuvelis D, Bidlack JM, Polt R, Bilsky EJ (2011) In vivo characterization of MMP-2200, a mixed δ/μ opioid agonist, in mice. J Pharmacol Exp Ther 336:767–778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lynch WJ, Nicholson KL, Dance ME, Morgan RW, Foley PL (2010) Animal models of substance abuse and addiction: implications for science, animal welfare, and society. Comp Med 60:177–188

    CAS  PubMed  PubMed Central  Google Scholar 

  • Matsuoka Y, Furuyashiki T, Yamada K, Nagai T, Bito H, Tanaka Y, Kitaoka S, Ushikubi F, Nabeshima T, Narumiya S (2005) Prostaglandin E receptor EP1 controls impulsive behavior under stress. Proc Natl Acad Sci USA 102:16066–16071

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mckendrick G, Graziane NM (2020) Drug-induced conditioned place preference and its practical use in substance use disorder research. Front Behav Neurosci 14:582147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mckendrick G, Garrett H, Jones HE, Mcdevitt DS, Sharma S, Silberman Y, Graziane NM (2020) Ketamine blocks morphine-induced conditioned place preference and anxiety-like behaviors in mice. Front Behav Neurosci 14:75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Morgan MM, Christie MJ (2011) Analysis of opioid efficacy, tolerance, addiction and dependence from cell culture to human. Br J Pharmacol 164:1322–1334

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moussawi K, Ortiz MM, Gantz SC, Tunstall BJ, Marchette RCN, Bonci A, Koob GF, Vendruscolo LF (2020) Fentanyl vapor self-administration model in mice to study opioid addiction. Sci Adv 6:eabc0413-eabc0413

    Article  CAS  Google Scholar 

  • Negus SS, Rice KC (2009) Mechanisms of withdrawal-associated increases in heroin self-administration: pharmacologic modulation of heroin vs food choice in heroin-dependent rhesus monkeys. Neuropsychopharmacology 34:899–911

    Article  CAS  PubMed  Google Scholar 

  • Nielsen CK, Ross FB, Smith MT (2000) Incomplete, asymmetric, and route-dependent cross-tolerance between oxycodone and morphine in the dark agouti rat. J Pharmacol Exp Ther 295:91–99

    CAS  PubMed  Google Scholar 

  • Olson ME, Eubanks LM, Janda KD (2019) Chemical interventions for the opioid crisis: key advances and remaining challenges. J Am Chem Soc 141:1798–1806

    Article  CAS  PubMed  Google Scholar 

  • Richardson KA, Yohay AL, Gauda EB, Mclemore GL (2006) Neonatal animal models of opiate withdrawal. ILARJ 47:39–48

    Article  CAS  Google Scholar 

  • Rutten K, Van Der Kam EL, De Vry J, Tzschentke TM (2011) Critical evaluation of the use of extinction paradigms for the assessment of opioid-induced conditioned place preference in rats. Pharmacology 87:286–296

    Article  CAS  PubMed  Google Scholar 

  • Sakae DY, Martin SJ (2019) Formation of a morphine-conditioned place preference does not change the size of evoked potentials in the ventral hippocampus–nucleus accumbens projection. Sci Rep 9:5206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schiller PW, Fundytus ME, Merovitz L, Weltrowska G, Nguyen TMD, Lemieux C, Chung NN, Coderre TJ (1999) The opioid μ agonist/δ antagonist DIPP-NH2[Ψ] produces a potent analgesic effect, no physical dependence, and less tolerance than morphine in rats. J Med Chem 42:3520–3526

    Article  CAS  PubMed  Google Scholar 

  • Shook JE, Lemcke PK, Gehrig CA, Hruby VJ, Burks TF (1989) Antidiarrheal properties of supraspinal mu and delta and peripheral mu, delta and kappa opioid receptors: inhibition of diarrhea without constipation. J Pharmacol Exp Ther 249:83–90

    CAS  PubMed  Google Scholar 

  • Starnowska J, Costante R, Guillemyn K, Popiolek-Barczyk K, Chung NN, Lemieux C, Keresztes A, Van Duppen J, Mollica A, Streicher J, Vanden Broeck J, Schiller PW, Tourwé D, Mika J, Ballet S, Przewlocka B (2017) Analgesic properties of opioid/NK1 multitarget ligands with distinct in vitro profiles in naive and chronic constriction injury mice. ACS Chem Neurosci 8:2315–2324

    Article  CAS  PubMed  Google Scholar 

  • Stein C (2018) New concepts in opioid analgesia. Expert Opin Investig Drugs 1–11

    Google Scholar 

  • Stone LS, German JP, Kitto KF, Fairbanks CA, Wilcox GL (2014) Morphine and clonidine combination therapy improves therapeutic window in mice: synergy in antinociceptive but not in sedative or cardiovascular effects. PLoS One 9:e109903–e109903

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Van Den Hoogen RH, Colpaert FC (1986) Respiratory effects of morphine in awake unrestrained rats. J Pharmacol Exp Ther 237:252–259

    PubMed  Google Scholar 

  • Venniro M, Banks ML, Heilig M, Epstein DH, Shaham Y (2020) Improving translation of animal models of addiction and relapse by reverse translation. Nat Rev Neurosci 21:625–643

    Article  CAS  PubMed  Google Scholar 

  • Walker EA, Chambers C, Korber MG, Tella SR, Prioleau C, Fang L (2021) Antinociceptive and discriminative stimulus effects of six novel psychoactive opioid substances in male rats. J Pharmacol Exp Ther 379:1–11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu F-X, Babazada H, Gao H, Huang X-P, Xi C-H, Chen C-H, Xi J, Yu W-F, Liu R (2019) Dezocine alleviates morphine-induced dependence in rats. Anesth Analg 128:1328–1335

    Article  CAS  PubMed  Google Scholar 

  • Yamashita M, Sakakibara Y, Hall FS, Numachi Y, Yoshida S, Kobayashi H, Uchiumi O, Uhl GR, Kasahara Y, Sora I (2013) Impaired cliff avoidance reaction in dopamine transporter knockout mice. Psychopharmacology 227:741–749

    Article  CAS  PubMed  Google Scholar 

  • Young-Mccaughan S, Miaskowski C (2001) Definition of and mechanism for opioid-induced sedation. Pain Manag Nurs 2:84–97

    Article  CAS  PubMed  Google Scholar 

  • Zamarripa CA, Naylor JE, Huskinson SL, Townsend EA, Prisinzano TE, Freeman KB (2020) Kappa opioid agonists reduce oxycodone self-administration in male rhesus monkeys. Psychopharmacology 237:1471–1480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang L-S, Wang J, Chen J-C, Tao Y-M, Wang Y-H, Xu X-J, Chen J, Xu Y-G, Xi T, Hu X-W, Wang Y-J, Liu J-G (2015) Novel κ-opioid receptor agonist MB-1C-OH produces potent analgesia with less depression and sedation. Acta Pharmacol Sin 36:565–571

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia

    M. Z. Imam, A. Kuo & M. T. Smith

Authors
  1. M. Z. Imam
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  2. A. Kuo
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  3. M. T. Smith
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Correspondence to M. T. Smith .

Editor information

Editors and Affiliations

  1. CorDynamics, Dieburg, Hessen, Germany

    Franz J. Hock

  2. CorDynamics, Chicago, IL, USA

    Michael R. Gralinski

  3. Cytokinetics (United States), South San Francisco, CA, USA

    Michael K. Pugsley

Section Editor information

  1. self employes, Dieburg, Deutschland

    Franz J. Hock DSc

  2. CorDynamics, Chicago, IL, USA

    Michael R. Gralinski Ph.D.

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Imam, M.Z., Kuo, A., Smith, M.T. (2022). Side Effects of Central Analgesic Drugs. In: Hock, F.J., Gralinski, M.R., Pugsley, M.K. (eds) Drug Discovery and Evaluation: Safety and Pharmacokinetic Assays. Springer, Cham. https://doi.org/10.1007/978-3-030-73317-9_70-1

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  • DOI: https://doi.org/10.1007/978-3-030-73317-9_70-1

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  • Print ISBN: 978-3-030-73317-9

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