Atypical Opioids Opiophobia. The Tragedy of Needless Pain

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1 Disclosure Atypical Opioids Stephan A Schug The Anaesthesiology Unit of the University of Western Australia, but not Professor Schug personally, has received research and travel funding and speaking and consulting honoraria from Eli Lilly, Grunenthal, ix Biopharma, Indivior and Seqirus within the last 2 years. Anaesthesiology & Pain Medicine University of Western Australia Royal Perth Hospital Opiophobia customary underutilisation of opioids for unfounded fears of creating dependence and addiction The Tragedy of Needless Pain What, though, should be done for people who suffer from debilitating chronic pain but who do not have a fatal illness? These people have traditionally been excluded from longterm therapy with narcotics, again for fear they would become addicts. Ron Melzack in SCIENTIFIC AMERICAN 1990; 262 (2) Morgan, Adv Alcohol Substance Abuse 1985;5:163 Chronic opioid therapy in non-malignant pain Russell Portenoy (& Kathleen Foley) JPSM 1990; 5(suppl. 1): S46 Australia is in the Red! 1

2 8 Sydney Sydney Morning Morning Herald Herald August 2018 Roxburgh, A., Dobbins, T., Degenhardt, L., and Peacock, A. (2018). Opioid, Amphetamine, and Cocaine-Induced Deaths in Australia: August 2018: Sydney, NDARC, UNSW. Conclusions of RCTs in Chronic Back Pain Opioids in Chronic Pain Draft Report US Agency for Health Care 2014 Unlikely to yield psychological or functional improvement. Moulin et al. Lancet 1996;347:143 There is only an insignificant improvement of quality of life as a result of morphine treatment. Klinger et al. 8 th World Congress 1996; P 50 opioid therapy is palliative and without long-term benefit. Jamison et al. Spine 1998;23:2591 Conclusions: Evidence on long-term opioid therapy for chronic pain is very limited but suggests an increased risk of serious harms that appears to be dose-dependent. Effect of Long-Term Opioid Therapy on Pain Perception Cohen et al., RAPM 2008;33:199 2

3 OPIAD - OPioid-Induced Androgen Deficiency Clinical Manifestations and Mechanisms Mechanism of OPIAD Typical symptoms of OPIAD Direct inhibition of GnRH secretion with reduced sexual hormone levels (e.g. testosterone, LH, FSH) Vasomotor instability Depression Anemia Osteoporosis Menstrual irregularities Fatigue Hot flashes Decreased muscle mass Weight gain Reduced libido Erectile dysfunction GnRH = gonadotropin-releasing hormone; LH = luteinizing hormone; FSH = follicle-stimulating hormone Kienbaum P, et al. Circulation. 2001; Herbison AE. Rev Reprod. 1997; Nicoletti I, et al. J Clin Endocrinol Metab. 1981; Schule C, et al. Psychoneuroendocrinology. 2004; Terasawa E, et al. Endocrinology the categorization of all analgesics that have any component of opioid mechanism of action into the same class is anachronistic. something that belongs to the past rather than the present Atypical Opioids The authors discussed the 4 atypical opioids that have been recently developed, which include buprenorphine, cebranopadol, tapentadol, and tramadol. They explained, These agents rely on unique and possibly synergistic mechanisms of action and do not work like conventional opioids, yet they are often categorized as opioids, which can be misleading in that they have different attributes than conventional opioids. not registered in Australia Pergolizzi JP, LeQuant J, Taylor R, Raffa R. The Introduction of a New Term: Multigesics. NEMA Research Group. Naples, FL, USA. 17 Buprenorphine has a unique and complex pharmacology. - partial µ-agonist in vitro, full µ-agonist clinically - activates distinct subset of G-protein - kappa receptor antagonist, acts as chaperone ligand - opioid receptor like 1 (ORL1) agonist 3

4 Advantages of Buprenorphine Tramadol An Atypical Centrally Acting Analgesic Effective analgesic with no analgesic ceiling effect Less OIH due to less glia activation Ceiling effect on respiratory depression Less constipation than other opioids Less cognitive dysfunction than other opioids Less immunesuppression than other opioids Less OPIAD than other opioids Safer than other opioids in the elderly Milder withdrawal than other opioids Less drug dependence than other opioids Safe in renal failure Davis J Support Oncol. 2012;10(6): % µ-agonist 5HT uptake inhibition 20% NA uptake inhibition 40% Schug SA. Ther Clin Risk Manage 2007:3(5) Advantages of Tramadol Disadvantages of Tramadol Good efficacy in neuropathic pain (2 nd line treatment) Low risk of respiratory depression M1 related (renal failure, ultrafast metaboliser) Less constipation than conventional opioids Less immunesuppression than conventional opioids Less physical dependence than conventional opioids Milder withdrawal Less drug dependence and abuse than conventional opioids Mioto et al. Anesth Analg 2017 ;124(1):44-51 MacLean et al. Expert Rev Neurother. 2015;15(5): Rosenberg et al. Int J Clin Pract. 2009;63(10): Analgesic effect limited µ-agonist effect of M1 is CYP450 2D6 dependent Serotonergic component of effect problematic More nausea and vomiting More confusion, in particular in elderly patients Possibly increased seizure risk Risk of serotonergic reactions Potential interaction with TCAs SSRIs SNRIs Mioto et al. Anesth Analg 2017 ;124(1):44-51 Schug SA. Ther Clin Risk Manage 2007:3(5) MacLean et al. Expert Rev Neurother. 2015;15(5): Rosenberg et al. Int J Clin Pract. 2009;63(10): Tapentadol: Mechanisms of Action µ-receptor Agonism and Noradrenaline Reuptake Inhibition MOR (µ-opioid receptor agonist) NRI (Noradrenaline reuptake inhibitor) TAP Ascending pathway TAP Descending NA pathway Pain signal Pain signal Complementary MOR-NRI activity (site/mechanistic synergy): reduction of ascending pain signals enhancement of descending inhibitory pain control Tzschentke TM, et al. Drugs Future 2006;31: , Tzschentke TM, et al. JPET 2007;323: , Schröder et al. JPET 2011; 337: , Kress HG. Eur J Pain 2010; 14(8): British Journal of Anaesthesia 113 (1): (2014) 4

5 % patients experiencing 1 TEAE Change from baseline in SF-36 health survey score Tapentadol Equianalgesic to Conventional Opioids, But NOT Equiopioid Significantly greater improvement in 7 of 8 functional health measures compared with oxycodone CR Pooled analysis: SF-36 health survey Placebo(N=991) Approximate equianalgesic dose ratios 3,5,6 Morphine CR (oral): Palexia SR 1 : 3 Oxycodone CR : Palexia SR 1 : NS Tapentadol SR mg BD (N=978) Oxycodone CR 20-50mg BD (N=999) 0 Physical functioning Role physical Bodily Pain General Health Vitality Social functioning Role emotional Mental health Mental component summary physical component summary 1. Palexia SR Approved Product Information, 27 March Hunter New England Health (2014). Dose Equivalence & opioid rotation (Faculty of Pain Management). Available at: Accessed Jan Kress HG. Et al. Pain Physician 2014; 17(4): Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd; Galvez R et al. Adv Ther 2013; 30(3): Lange B et al. AdvTher 2010; 27(6): p Palexia SR vs oxycodone CR NS = Not significant Palexia SR vs oxycodone CR Results are presented for the ITT population (N=2968), last observation carried forward for the comparison of PALEXIA SR vs oxycodone CR. SF-36=Short Form (36) Health Survey. 1. Lange B, et al. Advanced Therapeutics 2010;27(6): Grunenthal data on file Quality of Life Scores in Patients with OA or Chronic Back Pain In a Meta-Analysis of RCTs Significantly lower incidence of GI-related side effects compared to oxycodone CR Placebo (n=993) Tapentadol SR mg bd (n=980) Oxycodone CR mg bd (n=1001) p<0.001 for Palexia SR vs oxycodone CR p-values not reported Lange B, et al. Advanced Therapeutics 2010;27(6): Tapentadol and OPIAD Baron et al. Pain Practice (5)

6 32 Toxicity of Tapentadol: A systematic review Australian Data: Opioid Related Fatalities Fatal events Four to five deaths from single-drug tapentadol use. A further ten deaths were identified as tapentadol mixeddrug deaths. Conclusions Tapentadol is unlikely to cause serotonin syndrome, and no cases have been established. The rate of tapentadol toxicity and in particular fatalities is orders of magnitudes less than that of conventional opioids such as oxycodone #. Channell & Schug, Pain Management Epub ahead of print 2018 A causal relationship has not been established. There have been isolated cases of serotonin syndrome in a temporal connection with tapentadol in combination with serotoninergic medicinal products # These statistics are based largely on assumptions, and further research is needed to calculate the real risk and relative risk of death and serious TEAE caused by tapentadol use and abuse. National Coronial Information System: Data Report DR Diversion Tamper-proof in USA Per 100,000 dosing units dispensed (C) from the fourth quarter (Q) of 2011 to the second Q of Tapentadol is the comparator and represented by the vertical line at 1. SR data from US may not reflect that in Australia Vosburg et al.journal of Pain, Vol 19, No 4 (April), 2018: pp 439- Dart et al, Pain Med

7 Conclusions In chronic pain, the role of conventional opioids is limited in view of the sociopsychobiomedical nature of chronic pain Current overuse of conventional opioids in the setting of chronic pain has lead to poor treatment of chronic pain and increased risks of abuse, diversion and overdoses The atypical opioids buprenorphine, tramadol and tapentadol should be the preferred opioids in chronic pain management These atypical opioids may also offer significant benefits in acute pain management 7