Conventional and atypical

Not all opioids are the same The atypical opioids: , and Use of opioids in chronic noncancer Acute and chronic musculoskeletal pain – pharmacological management Tapering off analgesia Opioid prescribing in general practice: a proposed approach

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SYDNEY OFFICE This supplement addresses concepts of chronic pain management and important 2/36 Bydown Street, principles of the use of opioids in this setting. Neutral Bay NSW 2089 POSTAL ADDRESS Professor Stephan Schug is Professor and Chair of Anaesthesiology PO Box 1473, Neutral Bay and Pain Medicine at the University of Western Australia; NSW 2089 and Director of Pain Medicine at Royal Perth Hospital, Perth, WA. TELEPHONE (02) 9908 8577 PAGE 5 FACSIMILE (02) 9908 7488 FEATURE ARTICLES PEER REVIEWED Printed by Blue Star Web, Sydney. Copyright 2018 Medicine Today Pty Ltd. No part of this publication may be reproduced, stored in a retrieval system, Not all opioids are the same 2 or transmitted in any form or by any means (electronic, mechanical or photocopy STEPHAN A. SCHUG recording or otherwise) in whole or in part, in any form whatsoever without the prior written permission of the Publisher. The atypical opioids: buprenorphine, tramadol The articles in this supplement and tapentadol 5 have been specially STEPHAN A. SCHUG PAGE 12 commissioned for this publication or were originally published in a Medicine Today Use of opioids in chronic noncancer pain 12 publication and updated. STEPHAN A. SCHUG, MIR WAIS SEKANDARZAD Each has been subjected to Medicine Today’s usual rigorous peer review process. Acute and chronic musculoskeletal pain – pharmacological This supplement has been management 16 sponsored by an unrestricted STEPHAN A. SCHUG, AHMAD AFIFI MOHD ARSHAD educational grant from Seqirus Pty Ltd. The opinions expressed in the articles are Tapering off opioid analgesia 23 PAGE 16 those of the authors and not APO DEMIRKOL necessarily those of Seqirus. Some products and/ or indications mentioned may not Opioid prescribing in general practice: a proposed be approved for use in approach 26 Australia. Please review Product Information, available MILTON L. COHEN, ALEX D. WODAK from the manufacturer, before prescribing any agent PAGE 26 mentioned in these articles.

MedicineToday ❙ Conventional and Atypical Opioids Supplement SEPTEMBER 2018 1

Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 EDITORIAL Not all opioids are the same STEPHAN A. SCHUG MD, FANZCA, FFPMANZCA, EDPM Opioids are the most effective available but when used inappropriately can cause problems to individual patients and society as a whole. Recognising the differences between conventional and atypical opioids can help prevent some of these adverse consequences.

pioids have been used by as nausea, vomiting, constipation, urinary humans for many thousands retention, sedation, confusion or agitation of years.1 Initially, these were have been well described.1,2 extracts of the poppy seed, Owhich were then chemically defined in Overcoming the fear of the form of and subsequently opioid use modified by the Initially opioids were freely available in to the wide range of medicines available many countries, but increasing concerns to us today. Opioids as we know them about abuse and addiction resulted in today differ in potency, restrictive legislation such as the Harrison and metabolism, but most rely primarily Act in the US in 1914.1 These con- on their activity on the mu-opioid cerns resulted in widespread ‘opiophobia’ receptor for their efficacy. among medical practitioners, other health- Opioids are the most effective analge- care professionals and even patients.3 This sics available and are mandatory compo- fear of creating addiction limited the use nents of pain relief in the setting of severe of opioids in appropriate settings such as acute pain, such as after surgery and for cancer pain, and was finally overcome trauma, or severe cancer pain. However, by the UK’s hospice movement and the opioids are not harmless and the poten- WHO’s recommendations for cancer pain tially life-threatening of management.4,5 However, these changes opioid-induced ventilatory impairment occurred primarily in developed and indus- (OIVI) and unpleasant side effects such trialised countries, whereas large parts of the world population still have insufficient access to opioids for the management of acute and cancer pain.6 Canada, the US and Australia, with sig- nificant consequences for patients and Opioids in chronic noncancer society as a whole.9,10 However, simply pain transferring the concepts and findings of In the 1990s, the success of increasing acute and cancer pain management to MedicineToday 2018; 19(9 Suppl): 2-4 opioid use for cancer pain led to sugges- the treatment of chronic noncancer pain tions that similar benefits could also be was regrettably a flawed concept. Professor Schug is Professor and Chair of achieved in patients with chronic non- In line with early concerns about this 7,8 Anaesthesiology and Pain Medicine, University of cancer pain. This resulted in a dramatic approach, managing the complexity of Western Australia; and Director of Pain Medicine at increase in the use of opioids for this the sociopsychobiomedical phenomenon Royal Perth Hospital, Perth, WA. indication in several countries including of chronic noncancer pain with opioids

2 MedicineToday ❙ Conventional and Atypical Opioids Supplement SEPTEMBER 2018

Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 often also show a deterioration of func- patients, but also for society as a whole.28 tion and quality of life with long-term opioid use.16,17 Not all opioids are the same The phenomenon of opioid-induced These dramatic consequences have led to hyperalgesia seems to increase central an interesting discussion about whether sensitisation and therefore the pain expe- all opioids are the same. Prominent rience in many patients, particularly those researchers in the area of opioid pharma- taking high doses of opioids.18,19 Further, cology, such as the pharmacologist adverse outcomes are caused by opioid-​ R. Raffa, have suggested that ‘categorisa- induced androgen deficiency (OPIAD) tion of all analgesics that have any com- leading to hypogonadotrophic hypo­ ponent of opioid gonadism with very low testosterone into the same class is anachronistic’.29 This levels and sequelae such as depression, suggests a separation of conventional (or fatigue, weight gain and decreased muscle classical) opioids, with their mechanism mass, contributing to further deteriora- of action primarily based on mu-opioid tion of the quality of life of patients receptor agonism, from atypical opioids, affected by chronic pain.20 which have multiple mechanisms of action Conventional mu-agonist opioids sup- and rely only partially on mu-receptor press immune function and this has clin- agonism. The substances buprenorphine, ical consequences with regard to increased tramadol, tapentadol and cebranopadol infection risk.21,22 The potential risk of fulfil this definition of atypical opioids. OIVI, leading to increased mortality among opioid users, is dose-dependent Atypical opioids and therefore increases when attempts to Three atypical opioids (buprenorphine, control pain lead to excessive dosing.23 tramadol and tapentadol) are currently Last, but not least, physical dependence, marketed in many countries worldwide, misuse and abuse and the development of while cebranopadol is undergoing phase addiction in susceptible patients have II trials.30 Research over the past 10 years become a serious problem in countries has increasingly shown that buprenor- with high opioid prescribing for chronic phine, in particular as a patch for trans- noncancer pain.24 dermal administration, as well as tramadol and tapentadol may have superior efficacy Effects of excessive opioid use in chronic pain, in particular with regard on society to the desired most relevant outcomes of In addition to the negative consequences improved function and quality of life.31-37 of inappropriate opioid use for many indi- In addition, they have less serious adverse viduals, there have also been harmful effects on immune function and the endo- consequences to society with increased crine system, lower rates of some other diversion of prescription opioids into the adverse effects (such as gastrointestinal black market and a dramatic increase in ones) and carry a reduced risk of OIVI, was not beneficial to many patients, par- deaths associated with prescription opioid and thereby death, in high doses.38-41 ticularly with long-term use.11-13 As shown misuse and abuse.24-26 Similar trends on a Finally, these atypical opioids have a lower in a wide range of randomised controlled smaller scale have now also been described abuse potential than conventional opioids trials summarised in meta-analyses, in European countries including France;27 and therefore a lower risk of misuse, abuse long-term opioid treatment of chronic however, the findings from Canada, the and diversion into black markets.40,42 noncancer pain results only in very lim- US and Australia are particularly worry- The recognition that there is a pro- ited pain relief and in particular almost ing.10 Overall, the ‘caring’ concept of found difference in efficacy, adverse no improvement in function and quality providing people experiencing chronic effects and safety between conventional of life.14,15 These disappointing outcomes pain with pain relief by prescribing them opioids and atypical opioids may offer have been confirmed in many observa- opioids has proven to have ‘crippling’ new and interesting avenues for the man- JOANNAMNUK/SHUTTERSTOCK

© tional and epidemiological studies, which consequences not just for the individual agement of chronic pain. MT

MedicineToday ❙ Conventional and Atypical Opioids Supplement SEPTEMBER 2018 3

Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 NOT ALL OPIOIDS ARE THE SAME continued

References of opioid dose and treatment duration on the tramadol. Clin Pharmacokinet 2004; 43: 879-923. 1. Schug SA. Opioids: clinical use. In: McMahon perception of a painful standardized clinical stimulus. 34. Schug SA. The role of tramadol in current Reg Anesth Pain Med 2008; 33: 199-206. SB, Koltzenburg M, Tracey I, Turk D, eds. Wall & treatment strategies for musculoskeletal pain. Ther 19. Bannister K. Opioid-induced hyperalgesia: Melzack’s textbook of pain. 6th ed. Amsterdam: Clin Risk Manag 2007; 3: 717-723. where are we now? Curr Opin Support Palliat Care Elsevier; 2013. 35. Rosenberg MT. The role of tramadol ER in the 2015; 9: 116-121. 2. Macintyre PE, Loadsman JA, Scott DA. Opioids, treatment of chronic pain. Int J Clin Pract 2009; 63: 20. O’Rourke TK, Jr., Wosnitzer MS. Opioid-induced ventilation and acute pain management. Anaesth 1531-1543. androgen deficiency (OPIAD): diagnosis, Intensive Care 2011; 39: 545-558. 36. Riemsma R, Forbes C, Harker J, et al. management, and literature review. Curr Urol Rep 3. Morgan JP. American opiophobia: customary Systematic review of tapentadol in chronic severe 2016; 17: 76. underutilization of opioid analgesics. Adv pain. Curr Med Res Opin 2011; 27: 1907-1930. 21. Ninkovic J, Roy S. Role of the mu-opioid Subst Abuse 1985; 5: 163-173. 37. Sanchez Del Aguila MJ, Schenk M, Kern KU, receptor in opioid modulation of immune function. 4. Zenz M, Willweber-Strumpf A. Opiophobia and Drost T, Steigerwald I. Practical considerations for Amino Acids 2013; 45: 9-24. cancer pain in Europe. Lancet 1993; 341: 1075-1076. the use of tapentadol prolonged release for the 22. Wiese AD, Griffin MR, Schaffner W, et al. Opioid 5. WHO. Cancer pain relief. Geneva: WHO; 1986. management of severe chronic pain. Clin Ther 2015; analgesic use and risk for invasive pneumococcal 6. Anderson T. The politics of pain. BMJ 2010; 341: 37: 94-113. diseases: a nested case-control study. Ann Intern c3800. 38. Bliesener N, Albrecht S, Schwager A, Med 2018; 168: 396-404. 7. Melzack R. The tragedy of needless pain. Sci Weckbecker K, Lichtermann D, Klingmuller D. 23. Vowles KE, McEntee ML, Julnes PS, Frohe T, Am 1990; 262: 27-33. Plasma testosterone and sexual function in men Ney JP, van der Goes DN. Rates of opioid misuse, 8. Portenoy RK. Chronic opioid therapy in receiving buprenorphine maintenance for opioid abuse, and addiction in chronic pain: a systematic nonmalignant pain. J Pain Symptom Manage 1990; dependence. J Clin Endocrinol Metab 2005; 90: review and data synthesis. Pain 2015; 156: 569-576. 5(1 Suppl): S46-S62. 203-206. 24. Davis WR, Johnson BD. Prescription opioid use, 9. Okie S. A flood of opioids, a rising tide of deaths. 39. Baron R, Jansen JP, Binder A, et al. , misuse, and diversion among street drug users in New N Engl J Med 2010; 363: 1981-1985. safety, and quality of life with tapentadol prolonged York City. Drug Alcohol Depend 2008; 92: 267-276. 10. Häuser W, Schug S, Furlan AD. The opioid release (PR) compared with / PR 25. Rintoul AC, Dobbin MD, Drummer OH, Ozanne- epidemic and national guidelines for opioid therapy in patients with severe chronic low back pain with a Smith J. Increasing deaths involving oxycodone, for chronic noncancer pain: a perspective from neuropathic component: a randomized, controlled, Victoria, Australia, 2000-09. Inj Prev 2011; 17: 254-259. different continents. PAIN Reports 2017; 2: e599. open-label, phase 3b/4 trial. Pain Pract 2016; 16: 26. Schatman ME, Ziegler SJ. Pain management, 11. Schug SA, Large RG. The use of opioids in 600-619. prescription opioid mortality, and the CDC: is the chronic pain of non-malignant origin. Pain - Clinical 40. Coplan PM, Sessler NE, Harikrishnan V, Singh devil in the data? J Pain Res 2017; 10: 2489-2495. Updates 1995; 3: 1-4. R, Perkel C. Comparison of abuse, suspected 27. Chenaf C, Kabore JL, Delorme J, et al. 12. Stein C. Opioid treatment of chronic suicidal intent, and fatalities related to the 7-day Prescription opioid analgesic use in France: trends nonmalignant pain. Anesth Analg 1997; 84: 912-914. buprenorphine transdermal patch versus other and impact on morbidity-mortality. Eur J Pain 2018 13. Carr DB, Bradshaw YS. Time to flip the pain opioid analgesics in the National Poison Data Jul 27; doi: 10.1002/ejp.1291 [epub ahead of print]. curriculum? Anesthesiology 2014; 120: 12-14. System. Postgrad Med 2017; 129: 55-61. 28. Large RG, Schug SA. Opioids for chronic pain of 14. Chaparro LE, Furlan AD, Deshpande A, Mailis- 41. Channell JS, Schug S. Toxicity of tapentadol: a non-malignant origin-caring or crippling. Health Care Gagnon A, Atlas S, Turk DC. Opioids compared with systematic review. Pain Manag 2018; Aug 6. doi: Anal 1995; 3: 5-11. placebo or other treatments for chronic low back 10.2217/pmt-2018-0027 [epub ahead of print]. 29. Raffa RB. On subclasses of opioid analgesics. pain: an update of the Cochrane Review. Spine 42. Vosburg SK, Severtson SG, Dart RC, et al. Curr Med Res Opin 2014; 30: 2579-2584. 2014; 39: 556-563. Assessment of tapentadol API abuse liability with the 30. Christoph A, Eerdekens MH, Kok M, Volkers G, 15. Chou R, Turner JA, Devine EB, et al. The researched abuse, diversion and addiction-related Freynhagen R. Cebranopadol, a novel first-in-class effectiveness and risks of long-term opioid therapy surveillance system. J Pain 2018; 19: 439-453. analgesic drug candidate: first experience in for chronic pain: a systematic review for a National patients with chronic low back pain in a randomized Institutes of Health Pathways to Prevention COMPETING INTERESTS: The Discipline of . Pain 2017; 158: 1813-1824. Workshop. Ann Intern Med 2015; 162: 276-286. Anaesthesiology and Pain Medicine at the University of 31. Davis MP. Twelve reasons for considering 16. Bostick GP, Toth C, Carr EC, et al. Physical Western Australia has received research and travel buprenorphine as a frontline analgesic in the functioning and opioid use in patients with funding and speaking and consulting honoraria from management of pain. J Support Oncol 2012; 10: . Pain Med 2015; 16: 1361-1368. Andros Pharmaceuticals, Aspen, bioCSL, Eli Lilly, 209-219. 17. Eriksen J, Sjogren P, Bruera E, Ekholm O, Grunenthal, Indivior, Janssen, Luye Pharma, 32. Khanna IK, Pillarisetti S. Buprenorphine - an Rasmussen NK. Critical issues on opioids in chronic Mundipharma, Pfizer, Pierre Fabre, Seqirus and iX non-cancer pain: an epidemiological study. Pain attractive opioid with underutilized potential in treatment Biopharma in the past five years. Professor Schug is a 2006; 125: 172-179. of chronic pain. J Pain Res 2015; 8: 859-870. member of the International and Australian Advisory 18. Cohen SP, Christo PJ, Wang S, et al. The effect 33. Grond S, Sablotzki A. Clinical pharmacology of Board for tapentadol.

4 MedicineToday ❙ Conventional and Atypical Opioids Supplement SEPTEMBER 2018

Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 PEER REVIEWED FEATURE The atypical opioids Buprenorphine, tramadol and tapentadol

STEPHAN A. SCHUG MD, FANZCA, FFPMANZCA, EDPM There are many differences between conventional and atypical opioids, including different , adverse effects and toxicities, as well as risk of abuse. These factors should be considered when prescribing opioids for chronic pain conditions.

hen the mechanism of action of tramadol was unravelled in the late 1990s, it became obvious that, KEY POINTS contrary to preceding beliefs that it is a partial mu-receptor agonist, it relies on multiple mecha- • Atypical opioids differ from conventional opioids as they do not rely exclusively on mu-receptor agonism for their Wnisms of action including weak mu-receptor agonism.1 This analgesic effect. recognition resulted in the early suggestion to describe tramadol • The atypical opioids, buprenorphine, tramadol and as an ‘atypical opioid’ in contrast to the conventional (or classical) tapentadol, have different effects and different adverse opioids. Subsequently, it became obvious that tramadol, and effects including toxicity and abuse potential compared also buprenorphine and tapentadol, have mechanisms of action with conventional opioids. that do not exclusively rely on mu-receptor agonism.2 • These differences result in improved outcomes and It has, therefore, been suggested that the atypical opioids reduced risks with the use of atypical opioids for buprenorphine, tramadol and tapentadol (as well as cebranopadol, individual patients and society as a whole. which is currently under investigation3), be classified separately • Atypical opioids are the preferred strong analgesics for from the conventional opioids such as morphine, oxycodone, chronic pain that requires pharmacological treatment. and . This separation is not only scien- • Tapentadol in particular seems to offer the best risk- benefit ratio in the pharmacological management of tifically useful on the basis of the different mechanisms of action, chronic pain with proven efficacy in nociceptive, but also clinically relevant as this translates into different efficacies, neuropathic and mixed pain conditions, best tolerability adverse effects and toxicity. It is the intention of this review to and good safety data. summarise the current knowledge about these atypical opioids.

Buprenorphine MedicineToday 2018; 19(9 Suppl): 5-11 Pharmacology Buprenorphine has the most complex pharmacology of the three 4 Professor Schug is Professor and Chair of Anaesthesiology and Pain Medicine, atypical opioids discussed here. Our understanding has changed University of Western Australia; and Director of Pain Medicine at Royal Perth over time, but this has not yet been fully elucidated. These issues SEBASTIAN KAULITZKI/SHUTTERSTOCK

© Hospital, Perth, WA. have resulted in some contradictory messages in the literature

MedicineToday ❙ Conventional and Atypical Opioids Supplement SEPTEMBER 2018 5

Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 THE ATYPICAL OPIOIDS continued

and significant confusion among clinical In comparative trials, buprenorphine has relevance is unclear.6 With regard to hypo- practitioners.5 Briefly, buprenorphine is a provided equivalent analgesia to morphine, gonadism and testosterone suppression potent but at the mu-opioid hydromorphone, oxycodone, fentanyl and (opioid-induced androgen deficiency), the receptor with high receptor affinity .7 The conversion from trans- effects of buprenorphine seem to be minimal explaining its long duration of action.6 It is dermal buprenorphine to oral morphine compared with conventional opioids.31 also a potent kappa-receptor antagonist.5 suggests an ratio in the range It has been shown in several studies that Furthermore, buprenorphine is an agonist of 1:110.5,16 Buprenorphine also has proven buprenorphine causes less cognitive dys- at the or opioid-­receptor-like 1 efficacy and low rates of toxicity in elderly function than conventional opioids with (ORL-1) receptor; the latter effects possibly patients and its effects are minimally regard to parameters such as visual pursuit explain some of the many advantageous affected by renal failure or haemodialysis.7 test and driving-related psychomotor bat- effects of buprenorphine.7 In addition, tery, as well as complex psychomotor and buprenorphine binds to delta-opioid Safety and adverse effects cognitive performance.7 These experimen- receptors. Buprenorphine has a ceiling effect for res- tal data may even translate into improved Overall, buprenorphine behaves quite piratory depression, and it is likely that clinical outcomes; in an epidemiological differently from conventional opioids with respiratory depression linked to bupre­ study buprenorphine was the only strong primarily mu-agonist effects. The inter- norphine is primarily caused by its active opioid not linked to an increased fracture play between these multiple receptor metabolite .17,18 The risk due to falls.32 Other advantages of effects is complex and species-specific. observation of this ceiling effect reduces the buprenorphine are less constipating effects, For example, the inverted U-shaped dose-​ risk of respiratory depression, but does not in particular when administered trans­ effect curve for buprenorphine that was mean that buprenorphine has no respiratory dermally, where it causes less constipation found in rodents led to concerns over a depressant effect;6 there are published than even transdermal fentanyl.6 Specific possible submaximal analgesic effect in reports of fatalities and significant respira- adverse effects of transdermal buprenor- humans, but this has not been confirmed tory depression with sublingual buprenor- phine are local skin reactions, in particular in clinical practice.5 phine.19,20 In this context it is of interest that, erythema and pruritus, which are more although combinations of buprenorphine common than with transdermal fentanyl Efficacy with a benzodiazepine increase the risk of and may be reduced by topical cortico­ Buprenorphine has been extensively inves- fatal outcomes,19 they seem to be safer than steroid administration.33 tigated as a sublingual preparation, in par- methadone with a benzodiazepine.21 With ticular for opioid substitution in the transdermal buprenorphine, respiratory Dependence, abuse potential and management of opioid addiction.8,9 In this depression with fatal consequences has a diversion setting, the analgesic effects of buprenor- zero incidence in a data analysis from the Buprenorphine is a partial mu-receptor phine are sufficient to cover severe post- US National Poison Data System.22 agonist, which results in ‘drug liking’ and operative pain, therefore leading to a With regard to long-term use, buprenor- is therefore associated with abuse potential, reversal of the previous advice to discon- phine seems to cause less tolerance than withdrawal and diversion in its sublingual tinue buprenorphine substitution before conventional mu-receptor such preparations.34 However, buprenorphine major surgery.10 Contrary to the findings as fentanyl.23 It has an antihyperalgesic is not as well ‘liked’ as full mu-receptor in animal experiments, all available data effect and may attenuate opioid-induced agonists. In particular, the transdermal on humans show no analgesic ceiling effect hyperalgesia, possibly due to less glial acti- preparation with stable plasma concentra- with no plateau of the dose-response curve vation via Toll-like receptor 4, an impor- tion seems to be unattractive for drug in clinically meaningful doses and no tant mechanism in central sensitisation seekers. This is confirmed by US data antagonistic effect of buprenorphine when and neuropathic pain, but also in opioid-­ showing that prescription-adjusted rates combined with other mu-agonists.11,12 induced hyperalgesia.24-26 of intentional abuse and suspected suicidal The high potency and good lipophilicity Conventional opioids have significant intent with transdermal buprenorphine of buprenorphine made it an ideal candi- immunosuppressive effects, which have were significantly lower than for mor- date for the development of transdermal been recently related to dose-dependent phine, oxycodone, , meth- delivery systems.13 Most value for the treat- increases in infection risk with long-term adone and transdermal fentanyl.22 ment of cancer and chronic noncancer pain opioid use.27,28 In the experimental setting, Physical dependence and withdrawal lies in use of these buprenorphine patches buprenorphine does not reduce natural symptoms occur with buprenorphine, but for transdermal application;14,15 the follow- killer cell activity and seems to be less immu- are reported as milder than with conven- ing text will primarily address transdermal nosuppressive;29,30 these data have not been tional opioids, e.g. in a double-blind com- buprenorphine, if not otherwise stated. confirmed in humans and their clinical parison with morphine;35 however, to

6 MedicineToday ❙ Conventional and Atypical Opioids Supplement SEPTEMBER 2018

Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 reduce these symptoms gradual dose analgesia, tramadol had comparable anal- tional opioids in routine clinical use.58,59 reduction is recommended.6 gesic efficacy to conventional mu-receptor The serotonergic effects of tramadol agonists such as morphine, fentanyl and lead to an increased risk of serotonergic Tramadol oxycodone.42 However, in clinical practice, reactions, and in rare cases serotonin syn- Pharmacology it has limited efficacy partially due to a drome, when combined with medications Tramadol is the prototype of the atypical recommended maximum dose of 400 to also having a serotonergic effect such as opioid and the first compound to be 600 mg daily. tricyclic antidepressants, selective serotonin described with this label in the literature.1 Tramadol has been successfully used reuptake inhibitors (SSRIs), serotonin and Tramadol has analgesic effects based on in patients with cancer pain as a step-two noradrenaline reuptake inhibitors (SNRIs) three mechanisms: the mu-receptor agonist drug on the WHO ladder, as well as in and monoamine oxidase inhibitors effect primarily of its main metabolite those with chronic noncancer pain, where (MAOIs).56,60 The risk is higher in people O-desmethyltramadol (M1), as well as it had also beneficial effects on physical who are CYP2D6 poor metabolisers and noradrenaline reuptake inhibition and function with reduced disability.43-45 In those taking SSRIs that inhibit CYP2D6 serotonin reuptake inhibition.36 Both of the osteoarthritis specifically, tramadol such as sertraline, paroxetine or fluoxe- latter mechanisms strengthen descending improved pain scores and function to tine, as both scenarios lead to increased pathways of pain control by increasing the some extent.46 Tramadol is also an effec- tramadol concentrations.60,61 Another synaptic concentration of inhibitory tive compound for the treatment of neu- relevant drug interaction is between tram- neurotransmitters.37 ropathic pain with a number needed to adol and 5-HT(3) receptor antagonist In animal experiments using appropri- treat of 3.8.47 It is the only opioid listed as antiemetics, described in particular for ate antagonists, about 40% of the analgesic a second-line treatment for neuropathic ondansetron.62 The interaction is most effect of tramadol was found to be based pain in the guidelines from the Special likely pharmacokinetic (via CYP2D6) and on mu-receptor agonism, about 40% on Interest Group on Neuropathic Pain.48 pharmacodynamic (via opposite effects noradrenaline reuptake inhibition and on serotonin effects) leading to reduced about 20% on serotonin reuptake inhibition Safety and adverse effects efficacy of both drugs.60,63,64 with synergism between these mecha- Due to the difference in pharmacology from The serotonergic effects of tramadol nisms.38 However, this may be different in conventional opioids, tramadol’s adverse resulted in an increased rate of nausea and humans, partially because the contribution effect profile also looks different. With vomiting in several comparative trials of the mu-receptor effect is mainly depend- regard to safety, the risk of respiratory with other conventional opioids such as ent on the active metabolite M1, which has depression is significantly lower than with morphine, fentanyl and oxycodone.42 An about 200 times greater affinity for the mu-­ the conventional opioids oxycodone and increased rate of confusion and delirium receptor than tramadol itself.37 The at equianalgesic doses.49-51 Tram- in elderly patients has also been described.65 O-demethylation of tramadol to M1 is adol does not depress the hypoxic ventilator Tramadol causes significantly less catalysed by cytochrome P450 (CYP) 2D6; response.52 However, it can cause respira- constipation than conventional opioids metabolisation is thereby dependent on the tory depression, particularly with overdose, primarily due to a less inhibitory effect on polymorphism of the gene encoding this and fatalities have been reported, although gastrointestinal motor function.37 Animal enzyme. People who are poor metabolisers the number of cases is very low.53 In this data support less immunosuppressive effects have significantly lower M1 plasma con- context, it might be important to consider of tramadol, which is not surprising in view centrations than extensive metabolisers.39 that the active metabolite M1 is excreted as of the low mu-receptor agonist effect of this This has been confirmed in studies showing a glucuronide via the kidney and therefore compound.66 Human data confirm this, that poor metabolisers required more tram- renal failure may lead to accumulation of but again there are no clinical outcome data adol to achieve the same analgesic effect this active metabolite.41,54 in line with these findings.67 and had a poorer analgesic response than Tramadol lowers the seizure threshold, extensive metabolisers.40 There might also most likely by its serotonergic effects.55,56 Dependence, abuse potential and be an increased risk for mu- Therefore, it causes more seizures than diversion effects such as respiratory depression in conventional opioids, particularly with Tramadol can cause physical dependence, ultra-fast metabolisers achieving high M1 overdose.53 This increased seizure risk was but with a lower incidence and lower plasma concentrations.41 also shown in comparison with tapentadol severity of withdrawal symptoms than in the US National Poison Data System.57 conventional opioids.68 Atypical with- Efficacy However, comparative epidemiological drawal symptoms similar to those In comparative trials with other opioids studies have not confirmed a higher seizure observed with SSRIs or SNRIs can also administered by patient-controlled rate for tramadol than those of conven- occur.69 Tramadol has been used

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successfully in opioid withdrawal and was tapentadol provides equianalgesic efficacy single-drug tapentadol overdose world- found to be superior to and to conventional opioids such as oxycodone wide over nine years, which is in stark comparable with buprenorphine in reduc- and morphine, the main comparators.81-83 contrast to, and orders of magnitude lower ing withdrawal symptoms.70 This efficacy can be shown across a spec- than, the mortality caused by conventional Although abuse of tramadol has been trum of nociceptive and neuropathic pain opioids.90 reported, the abuse potential is much lower states as well as mixed nociceptive- With regard to adverse effects, slow- than that of conventional opioids.37 These neuropathic pain.84 In neuropathic pain release tapentadol shows significant less findings are in line with US data, which states tapentadol improves neuropathic gastrointestinal adverse effects, namely show tramadol to have a comparable rate pain symptoms and quality of life. nausea, vomiting and constipation, than of diversion to tapentadol and a significantly Similarly, in contrast to conventional the slow-release preparation of the conven- lower rate than conventional opioids.71 This opioids such as oxycodone, tapentadol tional opioid oxycodone.81 These benefits is also supported by several extensive studies, significantly improves the quality of life remained when tapentadol was compared performed in particular in the US, leading of patients with chronic pain due to oste- with the slow-release combination of oxy- to a lower scheduling of tramadol than con- oarthritis and low back pain as shown in codone and naloxone in another study.91 ventional opioids in most countries;72,73 this a large pre-planned meta-analysis.81 This The medication is also extremely well tol- assessment has been confirmed by expert effect is seen across most domains of the erated in the elderly, with similar advan- committees, such as in Germany.74 SF-36 quality of life questionnaire and tages seen in patients aged older than thereby offers significant outcome advan- 75 years.92,93 In a network meta-analysis of Tapentadol tages in comparison with conventional the tolerability of opioid analgesics for Pharmacology opioids. In comparative trials, 5 mg oral chronic pain, tapentadol was the top rank- The analgesic effect of tapentadol is based tapentadol was equianalgesic to 1 mg oxy- ing analgesic due to the lowest incidence on its combined effect as a mu-opioid codone and 1 mg to 3.3 mg morphine.81,85,86 of overall adverse events, including consti- receptor agonist and a noradrenaline reup- However, as these are equianalgesic rates pation, and the lowest trial withdrawal take inhibitor.75 The affinity of tapentadol and tapentadol has a much lower mu- rate.94 for the human mu-receptor is about 18 receptor affinity than conventional opioids, In a three-month study, tapentadol times lower than that of morphine (but change from a conventional opioid to tap- showed significantly less testosterone sup- tapentadol is only three times less potent entadol has to be performed slowly over pression than oxycodone, with only 11% of than morphine), whereas the reuptake time. Direct immediate patients taking tapentadol compared with inhibition of noradrenaline is similar to leads to opioid withdrawal symptoms. The 46% of patients taking oxycodone presenting that of an SNRI such as venlafaxine. The rotation from tramadol to tapentadol, how- with testosterone levels below the normal high analgesic efficacy is explained by the ever, can be performed in one step and range.91 With regard to effects of tapentadol extensive synergy between the two mech- leads to better outcomes in most patients.87 on immune function, data are currently still anisms of action as shown in site-specific sparse, but, in contrast to conventional administration studies.76 This mechanism Safety and adverse effects opioids, short- and long-term tapentadol of action explains that tapentadol poten- In contrast to conventional opioids, tap- administration seems to maintain splenic tiates descending pain inhibition.77 entadol causes significantly less opioid- cytokines in animal experiments.95 Although often regarded as being similar induced ventilatory impairment. This has to tramadol, tapentadol differs with regard been confirmed in head-to-head compar- Dependence, abuse potential and to its almost complete lack of a serotonergic isons at equianalgesic doses with the diversion effect and the fact that metabolites do not conventional opioid oxycodone.88 More Physical dependence on tapentadol is lim- contribute to its analgesic effect.78,79 This relevantly, data from the US, where tap- ited and therefore withdrawal symptoms explains why no causal relationship between entadol has been available since 2009, occur rarely and are mild to moderate, tapentadol and serotonin syndrome has report no fatalities from tapentadol use in even with abrupt cessation.96 Tapentadol been established and there are no clinically a comparative analysis of the safety of abuse has been described, but rates are relevant drug interactions between tapen- various opioids.89 The same study also lower than with conventional opioids such tadol and antidepressants.80 showed that tapentadol had the lowest rate as oxycodone, suggesting a significantly of major medical adverse effects, hospi- lower potential for abuse.71,97-99 This has Efficacy talisations and serious adverse effects of been consistently shown for a considerable In settings of osteoarthritis, chronic low all opioids on the US market, including number of outcome parameters com- back pain, neuropathic pain due to dia- tramadol. A systematic literature review monly used to identify issues of abuse with betic polyneuropathy and cancer pain, identified four, possibly five, deaths from a medication.

8 MedicineToday ❙ Conventional and Atypical Opioids Supplement SEPTEMBER 2018

Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 An evaluation of the internet discus- pain. Tapentadol is equianalgesic to potent 10. Huxtable CA, Macintyre PE. An alternative way sion among recreational drug users in the conventional opioids and has the most of managing acute pain in patients who are in US, where tapentadol has been on the convincing evidence for a positive effect buprenorphine opioid substitution therapy market for more than nine years, revealed on multiple domains of quality of life.81 It programs. Eur J Anaesthesiol 2013; 30: 717-718. the lowest proportion of all posts were also has the best tolerability and the lowest 11. Pergolizzi J, Aloisi AM, Dahan A, et al. Current knowledge of buprenorphine and its unique discussing tapentadol and this was signif- rate of fatalities and serious adverse events pharmacological profile. Pain Pract 2010; 10: 428-450. icantly lower by orders of magnitude than of all opioids, possibly with the exception 12. Butler S. Buprenorphine-clinically useful but often 99 89,94 any other substance discussed. Endorse- of transdermal buprenorphine. Finally, misunderstood. Scand J Pain 2013; 4: 148-152. ment as a drug of abuse for tapentadol was its abuse potential is much lower than that 13. Evans HC, Easthope SE. Transdermal also the lowest and similar to tramadol. of conventional opioids. buprenorphine. Drugs 2003; 63: 1999-2010; In a post-marketing study of patients It will be interesting to see how a fourth discussion 1-2. assessed for substance-abuse treatment, atypical opioid, cebranopadol, currently 14. Naing C, Aung K, Racloz V, Yeoh PN. Safety and tapentadol abuse was rare and lower than under development, will compare with efficacy of transdermal buprenorphine for the relief for most other scheduled analgesics.98 these three established representatives of of cancer pain. J Cancer Res Clin Oncol 2013; 139: Tapentadol resulted in significantly lower this interesting class of analgesics.3 1963-1970. rates of doctor shopping (obtaining med- The current literature supports the 15. Plosker GL. Buprenorphine 5, 10 and 20 µg/h ication from multiple prescribers) than notion that if opioids are regarded as nec- transdermal patch: a review of its use in the management of chronic non-malignant pain. Drugs oxycodone.100 Tapentadol has, together essary and useful for the treatment of 2011; 71: 2491-2509. with tramadol, the lowest rate of diversion chronic pain states, atypical opioids should 16. Sittl R, Likar R, Nautrup BP. Equipotent doses of 2 of opioid analgesics in the US and an be preferred. transdermal fentanyl and transdermal 101 extremely low black-market price. These buprenorphine in patients with cancer and findings in the US have been confirmed References noncancer pain: results of a retrospective cohort in other markets including Australia. 1. 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prescribed daily doses of transdermal fentanyl and buprenorphine versus morphine. J Pharmacol Exp catecholamine concentrations, and hemodynamics. transdermal buprenorphine during treatment of Ther 2014; 348: 217-226. J Clin Anesth 1999; 11: 310-316. patients with cancer and noncancer pain in 36. Desmeules JA, Piguet V, Collart L, Dayer P. 52. Warren PM, Taylor JH, Nicholson KE, Wraith PK, Germany: results of a retrospective cohort study. Contribution of monoaminergic modulation to the Drummond GB. Influence of tramadol on the Clinical Therapeutics 2005; 27: 1022-1031. analgesic effect of tramadol. Br J Clin Pharmacol ventilatory response to hypoxia in humans. Br J 24. Koppert W, Ihmsen H, Korber N, et al. Different 1996; 41: 7-12. Anaesth 2000; 85: 211-216. profiles of buprenorphine-induced analgesia and 37. Grond S, Sablotzki A. Clinical pharmacology of 53. Hassanian-Moghaddam H, Farajidana H, antihyperalgesia in a human pain model. Pain 2005; tramadol. 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Tolerability of opioid both opioid-like and atypical withdrawal symptoms extended release in patients with chronic painful analgesia for chronic pain: a network meta-analysis. occur. Drug Alcohol Depend 2003; 69: 233-241. diabetic peripheral neuropathy. Diabetes Care 2014; Sci Rep 2017; 7: 1995. 70. Dunn KE, Tompkins DA, Bigelow GE, Strain EC. 37: 2302-2309. 95. Franchi S, Amodeo G, Gandolla M, Moschetti G, Efficacy of tramadol extended-release for opioid 83. Wiffen PJ, Derry S, Naessens K, Bell RF. Oral Panerai AE, Sacerdote P. Effect of tapentadol on withdrawal: a randomized clinical trial. JAMA tapentadol for cancer pain. Cochrane Database splenic cytokine production in mice. Anesth Analg Psychiatry 2017; 74: 885-893. Syst Rev 2015; (9): CD011460. 2017; 124: 986-995. 71. Vosburg SK, Severtson SG, Dart RC, et al. 84. Steigerwald I, Muller M, Davies A, et al. 96. Sanchez Del Aguila MJ, Schenk M, Kern KU, Drost Assessment of tapentadol API abuse liability with the Effectiveness and safety of tapentadol prolonged T, Steigerwald I. Practical considerations for the use of researched abuse, diversion and addiction-related release for severe, chronic low back pain with or tapentadol prolonged release for the management of surveillance system. J Pain 2018; 19: 439-453. without a neuropathic pain component: results of an severe chronic pain. Clin Ther 2015; 37: 94-113. 72. Cicero TJ, Adams EH, Geller A, et al. A open-label, phase 3b study. Curr Med Res Opin 97. Cepeda MS, Fife D, Ma Q, Ryan PB. Comparison postmarketing surveillance program to monitor 2012; 28: 911-936. of the risks of opioid abuse or dependence between Ultram (tramadol hydrochloride) abuse in the United 85. Kress HG, Koch ED, Kosturski H, et al. tapentadol and oxycodone: results from a cohort States. Drug Alcohol Depend 1999; 57: 7-22. Tapentadol prolonged release for managing study. J Pain 2013; 14: 1227-1241 73. Cicero TJ, Inciardi JA, Adams EH, et al. Rates of moderate to severe, chronic malignant tumor-related 98. Butler SF, McNaughton EC, Black RA. abuse of tramadol remain unchanged with the pain. Pain Physician 2014; 17: 329-343. Tapentadol abuse potential: a postmarketing introduction of new branded and generic products: 86. Mercadante S, Porzio G, Aielli F, et al. Opioid evaluation using a sample of individuals evaluated for results of an abuse monitoring system, 1994-2004. switching from and to tapentadol extended release substance abuse treatment. Pain Med 2015; 16: Pharmacoepidemiol Drug Saf 2005; 14: 851-859. in cancer patients: conversion ratio with other 119-130. 74. Radbruch L, Glaeske G, Grond S, et al. Topical opioids. Curr Med Res Opin 2013; 29: 661-666. 99. McNaughton EC, Black RA, Weber SE, Butler review on the abuse and misuse potential of tramadol 87. Kress HG, Koch ED, Kosturski H, et al. Direct SF. Assessing abuse potential of new analgesic and in Germany. Subst Abus 2013; 34: 313-320. conversion from tramadol to tapentadol prolonged medications following market release: an evaluation 75. Tzschentke TM, Christoph T, Kogel BY. The release for moderate to severe, chronic malignant of Internet discussion of tapentadol abuse. Pain mu-opioid receptor agonist/noradrenaline reuptake tumour-related pain. Eur J Pain 2016; 20: 1513-1518. Med 2015; 16: 131-140. inhibition (MOR-NRI) concept in analgesia: the case 88. van der Schrier R, Jonkman K, van Velzen M, et 100. Cepeda MS, Fife D, Vo L, Mastrogiovanni G, of tapentadol. CNS Drugs 2014; 28: 319-329. al. An experimental study comparing the respiratory Yuan Y. Comparison of opioid doctor shopping for 76. Christoph T, Schroder W, Tallarida RJ, De Vry J, effects of tapentadol and oxycodone in healthy tapentadol and oxycodone: a cohort study. J Pain Tzschentke TM. Spinal-supraspinal and intrinsic volunteers. Br J Anaesth 2017; 119: 1169-1177. 2013; 14: 158-164. mu-opioid receptor agonist-norepinephrine reuptake 89. Murphy DL, Lebin JA, Severtson SG, Olsen HA, 101. Dart RC, Surratt HL, Le Lait MC, et al. Diversion inhibitor (MOR-NRI) synergy of tapentadol in Dasgupta N, Dart RC. Comparative rates of and illicit sale of extended release tapentadol in the diabetic heat hyperalgesia in mice. J Pharmacol Exp mortality and serious adverse effects among United States. Pain Med 2016; 17: 1490-1496. Ther 2013; 347: 794-801. commonly prescribed opioid analgesics. Drug Saf 77. Niesters M, Proto PL, Aarts L, Sarton EY, 2018; 41: 787-795. COMPETING INTERESTS: The Discipline of Drewes AM, Dahan A. Tapentadol potentiates 90. Channell JS, Schug S. Toxicity of tapentadol: a Anaesthesiology and Pain Medicine at the descending pain inhibition in chronic pain patients systematic review. Pain Manag 2018; Aug 6. doi: University of Western Australia has received with diabetic polyneuropathy. Br J Anaesth 2014; 10.2217/pmt-2018-0027 [epub ahead of print]. research and travel funding and speaking and 113: 148-156. 91. Baron R, Jansen JP, Binder A, et al. Tolerability, consulting honoraria from Andros 78. Raffa RB, Buschmann H, Christoph T, et al. safety, and quality of life with tapentadol prolonged Pharmaceuticals, Aspen, bioCSL, Eli Lilly, Mechanistic and functional differentiation of release (PR) compared with oxycodone/naloxone Grunenthal, Indivior, Janssen, Luye Pharma, tapentadol and tramadol. Expert Opin PR in patients with severe chronic low back pain Mundipharma, Pfizer, Pierre Fabre, Seqirus and iX Pharmacother 2012; 13: 1437-1449. with a neuropathic component: a randomized, Biopharma in the past five years. Professor Schug 79. Faria J, Barbosa J, Moreira R, Queiros O, controlled, open-label, phase 3b/4 trial. Pain Pract is a member of the International and Australian Carvalho F, Dinis-Oliveira RJ. Comparative 2016; 16: 600-619. Advisory Board for tapentadol.

MedicineToday ❙ Conventional and Atypical Opioids Supplement SEPTEMBER 2018 11

Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 PEER REVIEWED FEATURE Use of opioids in chronic noncancer pain STEPHAN A. SCHUG MD, FANZCA, FFPMANZCA, EDPM MIR WAIS SEKANDARZAD MD, FANZCA, DESA

Opioids play a much smaller role in the management of chronic noncancer pain than they do in that of severe acute pain and cancer pain. They are beneficial in a small subset of patients with chronic noncancer pain but there are pharmacological, KEY POINTS psychological and societal concerns about their • There are pharmacological, psychological and societal current widespread use for this indication. concerns about the current widespread use of opioids for chronic noncancer pain. here has been a dramatic increase in recent years in the • Opioids should not be regarded as the sole approach use of opioids to treat chronic noncancer pain, particularly to managing chronic noncancer pain but as one in the US but also in Australia. This has led to increasing component of a multidisciplinary management plan. concerns about the usefulness versus risks of this approach, • They should only be used for this type of pain after an Tboth for the individual patient and society as a whole. This review initial trial with defined positive outcomes, in particular article outlines the controversies surrounding their use for treating improvement of function. chronic noncancer pain and summarises their role in this setting, • They are not intended as life-long treatment and should the risks and complications regarding their use for this type of pain be discontinued by tapering the dose when treatment and the goals of such treatment, and its initiation and long-term use. goals are reached (or aberrant drug-taking behaviour becomes obvious). Different pain states • If a decision to use opioids is made, atypical opioids Chronic noncancer pain is a heterogeneous disorder, characterised (transdermal buprenorphine, tramadol or tapentadol) by a wide spectrum of pain states ranging from physiological pain should be used in preference to conventional opioids. with nociceptive and inflammatory origin (e.g. osteoarthritis) to pathological pain states of either neuropathic origin (i.e. caused by damage or disease of the somatosensory system, e.g. diabetic poly- Some principles of opioid therapy in the acute pain and chronic neuropathy) or dysfunctional origin (i.e. no such damage/disease and cancer pain setting, where they have well accepted analgesic efficacy no noci­ception but caused by central sensitisation/insufficient endog- and a good safety profile, may be transferred to the setting of noci­ enous inhibition, e.g. fibromyalgia).1 It is therefore not surprising that ceptive and neuropathic pain, where their use can lead to improved the role of opioids in these different pain states is not the same. function and reduced pain in some patients, although long-term outcome data are limited or even contradictory.2,3 Dysfunctional pain states on the other hand are characterised primarily by central sen- MedicineToday 2018; 19(9 Suppl): 12-15 sitisation and limited endogenous inhibition, and seem to be poorly First published: PAIN MANAGEMENT TODAY 2014; 1(1): 25-28 responsive to opioid therapy. Furthermore, chronic pain is charac- Updated September 2018 terised as a sociopsychobiomedical phenomenon, and the wide array of psychosocial factors, such as catastrophising, anxiety, mood states Professor Schug is Professor and Chair of Anaesthesiology and Pain Medicine, including depression, suffering and dependence on the healthcare The University of Western Australia; and Director of Pain Medicine at Royal Perth system, are not really responsive to opioids and need to be addressed Hospital, Perth, WA. Dr Sekandarzad is Adjunct Senior Lecturer in Anaesthesiology by multimodal, multidisciplinary interventions.4 Single modality and Critical Care at the School of Medicine Central, The University of Queensland, opioid therapy in dysfunctional pain states is both less successful in

Brisbane, Qld. improving analgesia and functional outcome and also carries a © MEDI-MATION/SPL

12 MedicineToday ❙ Conventional and Atypical Opioids Supplement SEPTEMBER 2018

Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 significant risk of aberrant drug-taking behaviour and abuse. 1. OPIOID THERAPY: USEFUL REFERENCE MATERIAL Efficacy • Quick clinical guidelines for the use of opioids in patients with As indicated above, opioids might confer a benefit and have some chronic noncancer pain, which originated in WA and demonstrated efficacy in well-defined chronic pain states such as Queensland: www.health.qld.gov.au/__data/assets/pdf_ osteoarthritis and neuropathic pain.5-8 Despite opioids showing file/0032/374693/ddu_quick_guide.pdf ­effectiveness and published guidelines supporting their use in • A more detailed prescription opioid policy, agreed upon by ­osteoarthritis-related pain, a 2009 Cochrane review on the efficacy of the Faculty of Pain Medicine of ANZCA, the RACGP, RACP and opioids in osteoarthritis of the knee or hip found only small-to-moderate RANZCP: http://fpm.anzca.edu.au/documents/prescription- beneficial effects of opioids and an increased risk of adverse effects.2,9,10 opioid-policy.pdf Similarly, opioids are viewed in guidelines for neuropathic pain treat- • Examples of treatment contracts for an opioid medicine: ment as second- or third-line treatments because of their risk-benefit www.aci.health.nsw.gov.au/__data/assets/pdf_file/0018/ profile,11-13 and therefore should only be used if first-line drugs (such 212760/Opioid_treatment_agreement.pdf; OR as anti­convulsants and antidepressants) fail or are contraindicated. www.racgp.org.au/your-practice/guidelines/drugs-of- The overall evidence for efficacy of opioids in chronic noncancer dependence-a/appendix-d-example-practice-policies/ pain is even more disappointing. A 2010 Cochrane review on long-term D5-Practice-policy-–-Drugs-of-dependence-therapy-agreement opioid management of chronic noncancer pain that included a total of 4893 patients found only weak evidence for sustainable pain relief and an inconclusive benefit on functional improvement or quality of life.14 should also be mentioned.22 Attempts to treat this with increasing A similar outcome in relation to lack of improved pain control, function opioid doses can result in escalation of opioid doses without benefit for or quality of life in chronic noncancer pain patients treated with opioids the patient.18 This therefore needs to be differentiated from development was reported in a large epidemiological study from Denmark.15 of tolerance to opioids.23 Physiological dependence will also develop, In summary, the evidence in favour of use of opioids in the chronic but it and the potential withdrawal reactions can be overcome by noncancer pain setting is at best weak. This statement is further tapering opioid doses slowly instead of discontinuing abruptly. confounded by most trials assessing only short-term benefits, having There are rather contradictory and inconsistent data on the prev- methodological flaws and describing heterogeneous outcomes. alence of opioid abuse in patients using opioids for chronic noncancer pain. Addiction (‘psychological dependence’) is a behavioural pattern Risks and complications of opioid therapy of drug use, characterised by overwhelming involvement with the use The most serious complication of opioid use is opioid-induced venti- (‘compulsive use’) of a drug leading to physical, social and psychological latory impairment leading to death. Although this is unlikely to occur harm.24 A systematic review of trials of opioid therapy for chronic back in patients who are taking a stable dose of opioid for long-term treat- pain showed a prevalence of lifetime substance abuse in the order of ment, statistics for the US and Australia show a dramatic increase in 36 to 56% and of current aberrant medication use of 5 to 24% in these mortality linked to prescription opioids.16,17 Reasons for this increased patients.25 Similarly, in a recent study, one in three patients undergoing mortality include incorrect opioid prescribing by doctors and incorrect long-term treatment with opioids for chronic pain met DSM-IV criteria intake by patients, and also diversion with use by others and coad- for addiction.26 On the other hand, a Cochrane review from 2010 ministration with sedatives such as alcohol and benzodiazepines.18 reported an addiction rate of only 0.27% in patients undergoing long- Constipation is a major adverse effect of the long-term use of opioids term opioid therapy for chronic noncancer pain.14 Risk factors for the and seriously affects patients’ quality of life. Patients do not develop development of addiction are male gender, younger age, history of tolerance to opioid-induced constipation and need co-medication with substance abuse disorder, mental health problems and use of higher appropriate laxatives. Opioid preparations with a reduced risk of con- doses of opioids.26,27 stipation are transdermal patches or combinations with naloxone.19 Finally, there is a risk that long-term opioid therapy might contradict Nausea, vomiting, sedation and cognitive impairment are often only the goals of chronic pain management. These goals are not only pain short-term adverse effects; tolerance to these can develop and therefore reduction but also reduced pain behaviour, improved function and interference with work or driving as well as the increased risk of falls increased self-efficacy. Current data suggest that opioids are used occur primarily in periods of dose titration or dose escalation.20,21 particularly to treat patients who describe greater disability, distress Opioids, via direct effects on the mu-receptor, also cause significant and suffering and poorer functioning, which might set up a vicious impairments of immune and endocrine functions, particularly with cycle.25 Rather than promoting self-efficacy and an internalised locus long-term use. Impairment of endocrine function can lead to opioid-­ of control, opioid therapy leads to an externalised locus of control with induced androgen deficiency requiring testosterone substitution.18 increased dependence on the healthcare system, encouragement of The phenomenon of opioid-induced hyperalgesia, a paradoxical passivity and reinforcement of pain behaviour proven to be counter- increase in sensitivity to pain in patients on long-term opioid therapy, productive in patients with chronic pain.28

MedicineToday ❙ Conventional and Atypical Opioids Supplement SEPTEMBER 2018 13

Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 Opioids in chronic noncancer pain continued

approach. Pharmacological therapy should be initiated according to 2. OPIOID THERAPY: FACTORS TO CONSIDER BEFORE INITIATION* well-established guidelines, with and NSAIDs/cyclo- oxygenase (COX)-2 inhibitors being used in nociceptive pain states • Pain diagnosis/psychological assessment and anticonvulsants and/or antidepressants in neuropathic pain states. • Multidisciplinary pain treatment As a small subgroup of patients with chronic pain may benefit from • Assess baseline function and severity of pain opioid use, this treatment should not be denied. However, in view of the • Screen for addiction risk risks described above, the introduction of opioids to treat chronic non- 29,30 • Determine treatment goals (focus on functional and quality of cancer pain requires strict adherence to well-established guidelines. life improvement) Details of examples of a quick clinical guideline for the use of opioids • Explain risks and benefits of opioid therapy in patients with chronic noncancer pain, a prescription opioid policy • Opioid treatment contract with patient: informed consent, and a ­treatment contract for an opioid medicine are given in Box 1. rules for treatment and cessation, consequences of aberrant Opioids should not be considered as a first-line treatment or a single drug-taking behaviour treatment modality but as one component of multidisciplinary pain * Modified from multiple sources including references 3, 18 and 30. treatment. They should only be trialled after reasonable attempts at multidisciplinary pain management, including other pharmacological options, have failed. Their introduction requires a diagnosis of persistent Implementation of opioid therapy nociceptive-inflammatory pain (e.g. osteoarthritis) or neuropathic The basis of good chronic pain management is a multidisciplinary and pain, and even then they should only be considered second- or third- multimodal approach. Psychological therapy with emphasis on cognitive line treatment.18,31 They should not be used in dysfunctional pain behavioural strategies to enhance coping mechanisms and reduce states, including fibromyalgia, visceral and pelvic pain syndromes, psychological stressors and physical therapy that includes exercise headaches and nonspecific chronic low back pain. Factors to be taken programs and physiotherapy form integral components of such an into account before initiation of opioid therapy are listed in Box 2. Initiation of opioid therapy for chronic non- cancer pain should be in the form of a closely Therapeutic drug trial period • Single prescriber • Start with transdermal or • Designated pharmacy monitored trial period of about four weeks’ dura- slow-release oral opioids for • Stable doses tion of a transdermal or slow-release oral opioid. defined period Atypical opioids (i.e. transdermal buprenorphine or slow-release tramadol and tapentadol) are the preferred opioids in this setting.32 In comparison to conventional opioids, they have better effects • Regular review of the 4 ‘As’: Regularly review and assess on function and quality of life and reduced risks treatment outcomes – Analgesia of abuse, diversion and overdose fatality.33 Defin- • Improvement of pain, function – Activities itive endpoints such as improvement in quality and quality of life – Adverse effects • Adherence to treatment – Aberrant drug-taking of life and function, including mood, sleep, occu- conditions behaviour pational and recreational activities, should be as • Cease treatment if review important as simple pain reduction. Such end- unsatisfactory points along with risks, benefits and rules on supply should ideally be formulated as an opioid contract between the patient and the provider. Opioid dose adjustment or Failure to achieve these treatment goals on rea- rotation depending on efficacy and adverse effects • Cease by tapering opioid sonable opioid doses (less than 100 mg daily oral doses slowly morphine equivalent) deems the patient’s pain • Add clonidine if as not responsive to opioids and should lead to withdrawal symptoms an agreed termination of opioid treatment via • After initial trial period of four • Involve drug abuse tapering doses. An approach to the initiation of weeks service if relevant opioid therapy is summarised in Figure 1. • Decision on long-term treatment aberrant drug-taking If the agreed endpoints were reached, the behaviour dependent on treatment outcome patient should qualify for long-term treatment and adherence to rules with opioids; however, this should not be seen as Figure 2. Long-term treatment/maintenance a decision for life-long treatment. Long-term treat- Figure 1. Initiation of opioid therapy. opioid therapy. ment requires adherence to the opioid contract,

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Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 including a single prescriber, a ­designated pharmacy and no unauthor- 11. Attal N, Cruccu G, Baron R, et al; European Federation of Neurological ised escalation of doses. Regular monitoring of the patient should assess Societies. EFNS guidelines on the pharmacological treatment of neuropathic the four ‘As’ of pain treatment outcomes: Analgesia, Activities of daily pain: 2010 revision. Eur J Neurol 2010; 17: 1113-e88. 12. Dworkin RH, O’Connor AB, Audette J, et al. Recommendations for the living, Adverse effects and Aberrant drug-taking behaviour. An pharmacological management of neuropathic pain: an overview and literature approach to long-term opioid therapy is summarised in Figure 2. update. Mayo Clin Proc 2010; 85(3 Suppl): S3-S14. Indications for cessation of long-term opioid therapy are lack of 13. National Institute for Health and Clinical Excellence (NICE). Neuropathic improvement in function, lack of analgesia and aberrant drug-taking pain: the pharmacological management of neuropathic pain in adults in non- behaviour.18,31 specialist settings. NICE Clinical guidelines. No. 96. London: NICE; 2010. 14. Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic noncancer pain. Cochrane Database Syst Rev 2010; (1): CD006605. Conclusion 15. Eriksen J, Sjogren P, Bruera E, Ekholm O, Rasmussen NK. Critical issues on Opioids play a much lesser role in the management of chronic non- opioids in chronic non-cancer pain: an epidemiological study. Pain 2006; 125: cancer pain than they do in the management of severe acute pain and 172-179. cancer pain. Although they may be beneficial in a very small subset 16. Okie S. A flood of opioids, a rising tide of deaths. N Engl J Med 2010; 363: 1981-1985. of patients with chronic noncancer pain, who should not be denied 17. Rintoul AC, Dobbin MD, Drummer OH, Ozanne-Smith J. Increasing deaths treatment of their chronic condition, there are pharmacological, involving oxycodone, Victoria, Australia, 2000-09. Inj Prev 2011; 17: 254-259. psychological and societal concerns about their current widespread 18. Freynhagen R, Geisslinger G, Schug SA. Opioids for chronic non-cancer pain. use for this indication. Their use in the management of chronic BMJ 2013; 346: f2937. ­noncancer pain requires an established pain diagnosis, screening for 19. Reimer K, Hopp M, Zenz M, et al. Meeting the challenges of opioid-induced increased risk of abuse, a good doctor-patient relationship and constipation in chronic pain management – a novel approach. Pharmacology 2009; 83: 10-17. ­adherence to agreed rules, ideally formulated in a treatment contract 20. Wilhelmi BG, Cohen SP. A framework for ‘driving under the influence of drugs’ and preference of atypical opioids over conventional opioids. Opioids policy for the opioid using driver. Pain Physician 2012; 15(3 Suppl): ES215-ES230. should only be used after an initial trial with defined positive outcomes, 21. Söderberg KC, Laflamme L, Möller J. Newly initiated opioid treatment and in particular improvement of function; a failed trial should lead to the risk of fall-related injuries. A nationwide, register-based, case-crossover discontinuation by tapering the opioid dose. study in Sweden. CNS Drugs 2013; 27: 155-161. 22. Tompkins DA, Campbell CM. Opioid-induced hyperalgesia: clinically relevant or Opioids should never be regarded as the sole approach to chronic extraneous research phenomenon? Curr Pain Headache Rep 2011; 15: 129-136. noncancer pain but as one component of a multidisciplinary man- 23. Collett BJ. Opioid tolerance: the clinical perspective. Br J Anaesth 1998; 81: agement plan. Even if used with benefits, they are not intended as 58-68. life-long treatment and should be weaned when function has been 24. Savage SR. Assessment for addiction in pain-treatment settings. Clin J Pain stabilised (or aberrant drug-taking behaviour becomes obvious). This 2002; 18(4 Suppl): S28-S38. 25. Martell BA, O’Connor PG, Kerns RD, et al. Systematic review: opioid might be a particular challenge in the many patients who have been treatment for chronic back pain: prevalence, efficacy, and association with started on opioids inappropriately in the past. PMT addiction. Ann Intern Med 2007; 146: 116-127. References 26. Boscarino JA, Rukstalis MR, Hoffman SN, et al. Prevalence of prescription opioid-use disorder among chronic pain patients: comparison of the DSM-5 vs. 1. Woolf CJ. What is this thing called pain? J Clin Invest 2010; 120: 3742-3744. DSM-4 diagnostic criteria. J Addict Dis 2011; 30: 185-194. 2. Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E. Opioids for chronic 27. Edlund MJ, Steffick D, Hudson T, Harris KM, Sullivan M. Risk factors for noncancer pain: a meta-analysis of effectiveness and side effects. CMAJ clinically recognized opioid abuse and dependence among veterans using 2006; 174: 1589-1594. opioids for chronic non-cancer pain. Pain 2007; 129: 355-362. 3. Kalso E, Allan L, Dellemijn PL, et al. Recommendations for using opioids in 28. Large RG, Schug SA. Opioids for chronic pain of non-malignant origin – chronic non-cancer pain. Eur J Pain 2003; 7: 381-386. caring or crippling. Health Care Anal 1995; 3: 5-11. 4. Stein C. Opioid treatment of chronic nonmalignant pain. Anesth Analg 1997; 29. Stein C, Reinecke H, Sorgatz H. Opioid use in chronic noncancer pain: 84: 912-914. guidelines revisited. Curr Opin Anaesthesiol 2010; 23: 598-601. 5. Avouac J, Gossec L, Dougados M. Efficacy and safety of opioids for 30. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic osteoarthritis: a meta-analysis of randomized controlled trials. Osteoarthritis opioid therapy in chronic noncancer pain. J Pain 2009; 10: 113-130. Cartilage 2007; 15: 957-965. 31. Sng BL, Schug SA. The role of opioids in managing chronic non-cancer pain. 6. Eisenberg E, McNicol E, Carr DB. Opioids for neuropathic pain. Cochrane Ann Acad Med Singapore 2009; 38: 960-966. Database Syst Rev 2006; (3): CD006146. 32. Schug S. Not all opioids are the same. Med Today 2018; 19(9 Suppl): 2-4. 7. Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological 33. Schug S. The atypical opioids: buprenorphine, tramadol and tapentadol. treatment of neuropathic pain. Pain 2010; 150: 573-581. Med Today 2018; 19(9 Suppl): 5-11. 8. Hollingshead J, Duhmke RM, Cornblath DR. Tramadol for neuropathic pain. Cochrane Database Syst Rev 2006; (3): CD003726. 9. AGS Panel on Persistent Pain in Older Persons. The management of persistent COMPETING INTERESTS: Professor Schug: The Anaesthesiology Unit of The pain in older persons. J Am Geriatr Soc 2002; 50(6 Suppl): S205-S224. University of Western Australia, but not Professor Schug privately, has 10. Nuesch E, Rutjes AW, Husni E, Welch V, Juni P. Oral or transdermal opioids received research and consultancy funding from Grünenthal, CSL, Janssen for osteoarthritis of the knee or hip. Cochrane Database Syst Rev 2009; (4): Pharmaceuticals, Mundipharma, Pfizer, Phosphagenics and iX Biopharma CD003115. within the past five years. Dr Sekandarzad: None.

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Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 PEER REVIEWED FEATURE Acute and chronic musculoskeletal pain Pharmacological management STEPHAN A. SCHUG MD, FANZCA, FFPMANZCA, EDPM AHMAD AFIFI MOHD ARSHAD MB BCh, MMed(Anaesthesiology) A multimodal, multidisciplinary approach is required when managing patients with musculoskeletal pain. Nonopioid analgesics should be KEY POINTS trialled first and opioids then used with caution. • Musculoskeletal pain is common and has significant consequences for usculoskeletal pain is a major chronic musculoskeletal problems in Aus- affected patients and society as a burden on the psychosocial and tralia from 2008 to 2009. This included the whole. physical wellbeing of an indi- costs of pharmacological treatments and • Musculoskeletal pain is not purely 1 vidual. In 2015, musculoskele- joint replacements. nociceptive; peripheral inflammation Mtal conditions were the most common Musculoskeletal pain is caused by con- and central sensitisation processes, as chronic disorders in Australia and were ditions of the bones, muscles and their well as neuropathic components, largely managed in the primary care setting. attachments (i.e. tendons, ligaments and contribute. According to self-reported estimates in 2011 connective tissues), and arthritis (i.e. • Management of patients with these to 2012, 28% or 6.1 million people in Aus- joints).1,2 These conditions range in time conditions should be multimodal and tralia experienced chronic musculoskeletal frame from sudden-onset and short-lived multidisciplinary, not rely on pharmacological approaches alone, conditions, mainly arthritis.1 Of these, 14% problems to life-long chronic disorders. and follow principles of chronic had back pain, 8% chronic osteoarthritis Consequences of the pain include loss of disease management aiming for (OA), 3% osteoporosis and 2% rheumatoid dexterity and mobility, which explains why improved function. arthritis. Previous estimates have suggested musculoskeletal conditions are the most • Nonopioid analgesics, in particular 2 that $5.7 billion was spent on patients with common cause of disability. NSAIDs, play an important role in the It is estimated that 20% of primary care pharmacological management of visits are due to musculoskeletal disorders, patients with these conditions. and many practitioners feel uncomfortable • Opioids should be used with caution MedicineToday 2018; 19(9 Suppl): 16-22 managing patients with common problems and only after careful consideration in First published MEDICINE TODAY 2017; associated with these conditions.3 The issues patients with musculoskeletal pain; 18(1): 14-20 of managing affected patients are further tramadol, buprenorphine and tapentadol may be preferable. compounded by the fact that most are elderly Professor Schug is Chair of Anaesthesiology at • Adjuvants such as anticonvulsants (e.g. The University of Western Australia; and Director with significant comorbidities and increased ) and antidepressants (e.g. of Pain Medicine at Royal Perth Hospital, Perth, risk of adverse effects of medications. Most duloxetine) may play a previously WA. Dr Mohd Arshad is Pain Specialist and importantly, thorough clinical assessment underestimated role in the management Anaesthesiologist at the Pain Management Clinic, and investigations for underlying medical of patients with musculoskeletal pain. Hospital Sultanah Bahiyah, Malaysia. disease or chronic inflammatory conditions

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Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 that central sensitisation and, in particular, serotonergic and endocannabinoid systems neuropathic elements also play a significant also appears to be involved in its analgesic role in the background of musculoskeletal effect. pain.5 When used by patients with acute post- For example, it is widely accepted that operative pain, paracetamol is an effective in the joint, peripheral unremitting analgesic, with an NNT50% in the range inflammatory reactions cause peripheral of 3.6; that is, 3.6 patients need to be treated sensitisation, especially after an acute to achieve 50% pain reduction involving injury. Different­ types of mechano­ one patient compared with placebo.12 How- receptors in the joint, including polymodal ever, the results are much more disappoint- type IV receptors, are involved in local ing in patients with musculoskeletal pain sensitisation as seen in inflammatory con- conditions. A large randomised trial in ditions.6 Furthermore, subsequent central patients with acute back pain showed no neuronal plasticity causes perpetuation benefit of regular or on-demand paraceta- of pain; this process is now commonly mol on pain relief and time to recovery called central sensitisation.7 Functional compared with placebo.13 Similarly, a MRI studies (fMRI) and psychophysical meta-analysis of paracetamol use in quantitative sensory testing (QST) con- patients with chronic low back pain showed firm that increased activity in the central no beneficial effect on pain, function or nervous system is associated with skin quality of life.14 In the same meta-analysis, stimulation in patients with chronic OA.6,8 paracetamol improved pain and disability Pain signal amplification in the central in patients with OA of the hip and knee; nervous system augments pain perception however, although the effects were statis- leading to allodynia (non-noxious stimuli tically significant, they were too small to perceived as pain) and hyperalgesia be clinically important. These disappoint- (heightened response to painful­ stimuli). ing findings were confirmed in another Clinically, patients with dominant features network meta-analysis of pharmacological should be performed to avoid missing other of central sensitisation experience dispro- interventions in patients with OA of the diagnoses or stereotyping patients.4 portionate pain, fatigue, cognitive impair- knee; of all interventions analysed, para­ Common approaches to managing ment and other somatic symptoms such cetamol showed the poorest improvement, patients with musculoskeletal pain include as sleep deprivation, stress and anxiety. the only one that was not clinically mean- several pharmacological and nonpharma- Features of central sensitisation can be ingful.15 Although this does not mean that cological treatments, including pharma- identified by the use of the Central Sensi- paracetamol may not be useful in patients cotherapy, surgery, injections, physical tisation Inventory, which can then guide who respond well to it, it leads to a recon- therapy, psychological approaches such as clinicians in selecting the most appropriate sideration of most previous guidelines hypnosis, relaxation and cognitive behav- therapeutic approaches.9 Similarly, com- emphasising the role of paracetamol as ioural therapy, and complementary or ponents of neuropathic pain can be iden- first-line treatment in the setting of acute alternative medicines. Improved under- tified using screening questionnaires, such and chronic musculoskeletal pain.16 standing of pain physiology and the under- as the Leeds Assessment of Neuropathic Paracetamol combined with an NSAID lying neurobiology has improved patient Symptoms and Signs (LANSS) Pain Scale, is superior to either compound alone; this outcomes through the development of new the Douleur Neuropathique 4 (DN4) or has been shown in particular for the com- approaches, better analgesics and more the pain­DETECT questionnaire.10 bination of paracetamol and , advanced delivery techniques. available commercially.17,18 Similarly, the Nonopioid analgesics combinations of paracetamol with a weak Mechanisms of pain Paracetamol opioid such as codeine or tramadol are Early concepts focused on degenerative Paracetamol has no specific endogenous more effective than paracetamol on its own, wear and tear of the musculoskeletal ele- binding sites, hence the continuous debates shown mostly in patients with acute post- ments as the main underlying mechanism surrounding its mechanisms of action.11 operative pain.19,20 There are also some data of musculoskeletal pain, with inflamma- It seems to exert effects centrally, possibly on the efficacy of paracetamol and tram-

u 001-20-4996 tory factors leading to peripheral sensiti- via direct and indirect cyclo-­oxygenase adol combinations in patients with chronic 21 © MCDERMOTT PAIN MANAGEMENT 2015. US COPYRIGHT REGISTRATION # VA sation. However, more recent data suggest inhibition; the activation of spinal musculoskeletal pain.

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AN APPROACH TO LONG-TERM NSAID THERAPY FOR MUSCULOSKELETAL PAIN

NSAID therapy is considered for a patient with musculoskeletal pain

What is the patient’s underlying GI risk?

High GI risk Low GI risk

What is the patient’s underlying CV risk? What is the patient’s underlying CV risk?

High CV risk, High CV risk Low CV risk High CV risk, High CV risk Low CV risk on on aspirin

• Avoid NSAID if • Avoid NSAID if • + • Low-dose • , or • Any possible, or possible, or PPI celecoxib* • Low-dose nonselective • Low-dose • Naproxen + PPI, or celecoxib* NSAID celecoxib* + • Low-dose PPI celecoxib* + PPI

Abbreviations: CV = cardiovascular; GI = gastrointestinal; PPI = proton pump inhibitor. * Low-dose celecoxib is 200 mg daily. Adapted from BMC Med 2015; 13: 55.22

Systemic NSAIDs and the selective NSAIDs, cyclo-oxygenase combined with proton pump inhibitors The biological stress response that occurs (COX)-2 inhibitors. (PPI) in susceptible patients, but PPIs are after a trauma or surgery generates chem- The main concerns with short- and not protective for NSAID enteropathy.22 ical mediators such as prostaglandins, long-term use of nsNSAIDs are upper and Compared with the COX-2 inhibitor cele­ which contribute to acute pain and its mor- lower gastrointestinal (GI) events (i.e. ulcer- coxib, the nsNSAID plus a PPI bidities. A low-grade local or systemic ation, bleeding, perforation or NSAID caused more clinically significant upper inflammation may persist, explaining the enteropathy), risks of cardiovascular (CV) and lower GI events.28 The best gastro­ more complex pathophysiology of persis- events and renal impairment.26 Adverse protective combination in high-risk tent or chronic pain conditions.22,23 As such, renal effects increase in patients with pre- patients who had previous GI bleeding NSAIDs represent a sensible strategy for existing renal impairment, hypotension, is a COX-2 inhibitor plus a PPI.29 treating patients with acute and chronic hypovolaemia, concurrent use of nephro- In terms of CV risk, naproxen seems to musculoskeletal pain. toxic drugs and multiple NSAID use. Risks be associated with less harm from CV NSAIDs have an established analgesic of upper GI problems follow long-term and events compared with other nsNSAIDs.30 efficacy in the treatment of patients with short-term use of nsNSAIDs.24 However, celecoxib may have a similar rate acute postoperative pain.16 They are also COX-2 inhibitors selectively inhibit the of CV effects27 and may be an alternative to similarly effective in the treatment of those inducible isoenzyme COX-2, preserving naproxen with reduced GI adverse effects.22 with chronic low back pain and acute ankle function of the constitutional isoenzyme The Flowchart shows a risk-based algorithm sprain.24 In patients with OA, NSAIDs COX-1, which determines protective func- for the selection of the most appropriate provide clinically meaningful analgesia tions of prostaglandins, in particular in NSAID in various risk situations.22 superior to paracetamol and comparable the GI tract. Therefore, COX-2 inhibitors Even in patients with acute renal failure, with opioids.15,25 There seems to be no dif- show reduced GI adverse effects compared COX-2 inhibitors may be advantageous ference in efficacy between appropriate with nsNSAIDs.27 Upper GI events due to over nsNSAIDs. In a large case-control doses of nonselective NSAIDs (nsNSAIDs) ­nsNSAIDs are relatively reduced when study, the risk of renal impairment was

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Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 shown to increase with a decrease in evidence-based guidelines, for example in dose of 5 mcg/h. Furthermore, buprenor- cyclo-oxygenase selectivity, favouring elderly patients with chronic musculo­ phine shows a ceiling effect for respiratory the use of COX-2 inhibitors.31 skeletal pain, recommend chronic opioid depression but not analgesia with increasing Elderly populations are at increased risk therapy only with great caution and when doses, which might increase its relative of adverse events from NSAIDs. However, all other safer alternatives have not been safety;45 other advantages are less constipa- in a large retrospective study of an elderly effective or not suitable.40 Use of opioid risk tion, immune and androgen suppression. cohort in the USA, risks of falls, fractures assessment tools to identify patients at risk Last, but not least, it might cause less tolerance and hospital admissions were lower with of aberrant drug-related behaviours should and hyperalgesia than other opioids.46 nsNSAID and COX-2 inhibitor use than be considered.41 Buprenorphine patches at doses of 5 to with opioid use.32 Overall, all NSAIDs Specifically, in patients with chronic pain 20 mcg/h were reported as being effective showed a reduced relative risk of safety due to OA, strong opioids have not been or very effective with high treatment adher- events including mortality, challenging the found to be more effective than NSAIDs25 ence in a recent UK observational study in notion that opioids are safer in this age or, in some studies, than placebo.42 At the patients with chronic musculoskeletal group. same time, use of opioids resulted, as out- pain.47 The results were comparable with lined above, in more falls, fractures, hospital those seen with sustained-release tramadol Topical NSAIDs admissions and mortality than NSAID use in patients with musculoskeletal pain Topical NSAIDs are effective for the treat- in this high-risk elderly population.32 Other who had had no relief with nsNSAIDs.48 ment of patients with short-term exacer- adverse effects, which need to be considered Buprenorphine patches were also success- bation or acute attacks of localised pain, when using opioids in the long term include fully trialled in multimorbid patients with such as strains, sprains or sports injuries, opioid-induced androgen deficiency (lead- significant analgesic efficacy and tolerable which often occur in the setting of chronic ing to decreased testosterone levels and adverse effects.49 musculoskeletal pain. Application of a top- subsequent osteoporosis), immune suppres- ical gel of , ibuprofen, diclofenac sion and opioid-induced hyperalgesia, Atypical centrally acting analgesics: and , but not indomethacin, two ­paradoxically increasing pain levels.36­ tramadol and tapentadol to three times daily provides effective pain Controlled-release preparations or Tramadol is classified as an atypical cen- relief with systemic adverse effects compa- long-acting opioids are usually recom- trally acting analgesic. Its opioid effects are rable with placebo.33 Similarly, topical mended for prolonged treatment in patients from an active metabolite (M1) and its more diclofenac and ketoprofen can provide pain with chronic pain; however, recent guide- important analgesic efficacy results from relief in individuals with chronic pain due lines issued by the Centers for Disease Con- noradrenaline and serotonin reuptake to OA with adverse effects comparable with trol and Prevention (CDC) question this inhibition. This mechanism of action leads placebo.34 Topical rubefacients containing rationale. No evidence was found that con- to improved analgesia with reduced opioid salicylates seem not to be effective in people tinuous administration of controlled-­release side effects such as constipation and a lower with acute and chronic conditions.35 opioids is more effective or safer than inter- risk of respiratory depression and abuse.50 mittent use of immediate-release opioids It has been used with benefit in patients Opioids or reduces opioid misuse or addiction.43 If with OA.51,52 However, disadvantages of There is a worldwide ongoing debate on controlled-­release preparations are used, tramadol include serotonergic adverse the use of opioids for the treatment of peo- then abuse-­deterrent formulations such as effects such as nausea and vomiting, poten- ple with chronic pain of nonmalignant a slow-release oxycodone preparation tial interactions with other serotonergic origin.36 Issues are the limited efficacy in should be chosen.44 drugs (e.g. antidepressants) and the reliance this setting as well as problems with aber- Specifically, transdermal buprenorphine on the opioid effect of a metabolite. The rant use, abuse and diversion. The resulting and, even more so, the atypical centrally metabolic pathway to this metabolite is via epidemic of prescription opioid overdoses acting analgesics tramadol and tapentadol cytochrome (CYP) 450 2D6 and is thereby with an unacceptably high mortality in the may offer some advantages in the chronic dependent on the specific phenotype for USA37 and also in Australia38 suggest that pain setting. this enzyme in an individual patient.53 a more cautious approach to opioid use is The recently registered tapentadol over- required. In addition, chronic opioid use Transdermal buprenorphine comes most of these disadvantages because seems to relegate self-efficacy and promote Transdermal buprenorphine is widely used the molecule itself is an opioid agonist with an externalised locus of control, leading to in the setting of chronic musculoskeletal 18 times less affinity to human mu-­receptors further dependence on the healthcare sys- pain, particularly in elderly patients. One than morphine and strong noradrenaline tem thereby contradicting the functional advantage with using transdermal buprenor- reuptake inhibition with negligible effects goals of pain management.39 Therefore, phine is the option of starting at a very low on serotonin.54,55 Despite the weak opioid

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agonism, it can match the analgesic efficacy effects of tramadol and tapentadol due to in treating patients with fibromyalgia of morphine in a 3:1 (tapentadol to mor- their noradrenergic effects, described above, (off-label uses).71 phine) dose ratio and oxycodone in a 5:1 apply also to antidepressants, thereby In one randomised controlled trial in (tapentadol to oxycodone) dose ratio.56 strengthening descending pathways of pain patients with knee OA, pregabalin was In patients with chronic low back pain inhibition.62 found to be as effective as and or OA, a meta-analysis showed that the the combination of both was superior to analgesic effect of slow-release tapentadol Antidepressants each individual component with regard was noninferior to that of slow-release oxy- Duloxetine is a serotonin and noradrenaline to pain and improvements in Western codone.56 However, improvement of quality reuptake inhibitor (SNRI) antidepressant, Ontario and McMaster Universities of life measures were superior in the tapen- which has been extensively studied for use Osteo­arthritis Index (WOMAC) score.72 tadol group, which experienced significantly in patients with neuropathic pain regardless lower rates of GI adverse effects (i.e. nausea, of its disease origin; it is here recommended Overall principles of vomiting, constipation) and fewer treatment as a first-line treatment, although it is only pharmacological management discontinuations. These results were con- indicated for diabetic peripheral neuro- of musculoskeletal pain firmed in a network meta-analysis against pathic pain and chronic musculoskeletal The aim of medication use for pain control several other conventional opioids (i.e. pain.63 In patients with chronic knee OA is always to facilitate initiation of daily ­fentanyl, hydromorphone, morphine and and chronic low back pain, duloxetine is activities and break the cycle of persistent oxymorphone).57 Also, data from the USA effective compared with placebo, with sig- pain, which leads to fear-avoidance and so far suggest a significantly lower risk of nificant improvement seen in physical subsequent musculoskeletal decondition- abuse than with conventional opioid use.58 outcomes.64,65 With the accumulating evi- ing. Therefore, when managing musculo- dence for its efficacy, duloxetine has been skeletal pain in particular, the emphasis Symptomatic slow-acting included in the recently updated Osteoar- should be on the ultimate goal of improved drugs for osteoarthritis thritis Research Society International function. Pharmacological therapy should Guidelines from the European League (OARSI) guidelines for the nonsurgical never be used alone, but integrated into against Rheumatism (EULAR) for man- management of patients with chronic OA.66 multimodal and multidisciplinary man- aging patients with pain due to knee OA Commonly observed adverse effects of agement of the sociopsychobiomedical suggest compounds such as glucosamine duloxetine are nausea, fatigue and features of chronic pain and is only one and chondroitin sulfate should be used as constipation.67,68 component of such management.73 This an initial approach.59 A recent consensus Other SNRIs such as venlafaxine and approach requires a stepwise integration statement from the European Society for tricyclic antidepressants (TCAs) such as of broad modalities of nonpharmacological Clinical and Economic Aspects of Osteo- may be useful in managing and pharmacological treatments, based on porosis and Osteoarthritis (ESCEO) patients with neuropathic pain (off-label prioritisation of intervention.61,74 ­reiterated a similar endorsement. It placed uses); but there are no studies to support a particular emphasis on the use of a their use in patients with musculoskeletal Conclusion ­patented prescription formulation of a pain. Furthermore, TCAs are best avoided A therapeutic approach to musculoskeletal crystalline glucosamine and chondroitin in the elderly because their anticholinergic pain requires an understanding of the sulfate combination, for which high-­quality activity increases the cumulative risk of underlying pathophysiology, but also a evidence of its efficacy compared with cognitive impairment and mortality in this detailed exploration of the impact on the other formulations was provided.60,61 age group.69 individual patient’s life and therapeutic goals. Nonpharmacological approaches, in Adjuvants Anticonvulsants particular physical therapies and psycho- With the recognition that central sensiti- The anticonvulsants recommended as first- logical management, are an important sation and elements of neuropathic pain line treatment for patients with neuropathic component of such an approach. Pharma- contribute significantly to chronic pain are and pregabalin.63 As cological treatments can and need to com- musculo­skeletal and joint pain comes the modulators of the alpha-2 delta subunits of plement these approaches with the ultimate development of a new role for antidepres- voltage-gated calcium channels in the goal of improving a patient’s daily function sants and anticonvulsants in the manage- ­central nervous system, they diminish neu- and quality of life. ment of patients with these pain conditions.6 ronal calcium influx and reduce release of In chronic pain states, long-term con- For example, pregabalin is now indicated excitatory neurotransmitters, primarily tinuation of pharmacological treatments for neuropathic pain and duloxetine for glutamate, and thereby reduce central has to be balanced against their potential ­diabetic polyneuropathy. The beneficial ­sensitisation.70 They are, therefore, effective adverse effects and complications. The

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Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 12. Moore RA, Derry S, McQuay HJ, Wiffen PJ. Single Faculty of Pain Medicine; 2015. recent recognition of elements of neuro- dose oral analgesics for acute postoperative pain in 25. Smith SR, Deshpande BR, Collins JE, Katz JN, pathic pain and central sensitisation con- adults. Cochrane Database Syst Rev 2011; (9): Losina E. Comparative pain reduction of oral non- tributing to musculoskeletal pain states has CD008659. steroidal anti-inflammatory drugs and opioids for opened new therapeutic avenues. MT 13. Williams CM, Maher CG, Latimer J, et al. Efficacy knee osteoarthritis: systematic analytic review. of paracetamol for acute low-back pain: a double- Osteoarthritis Cartilage 2016; 24: 962-972. References blind, randomised controlled trial. Lancet 2014; 26. Labianca R, Sarzi-Puttini P, Zuccaro SM, 1. Australian Institute of Health and Welfare 384: 1586-1596. 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38. Rintoul AC, Dobbin MD, Drummer OH, Ozanne- metaanalysis. J Rheumatol 2007; 34: 543-555. 64. Chappell AS, Ossanna MJ, Liu-Seifert H, et al. Smith J. Increasing deaths involving oxycodone, 52. Schug SA. The role of tramadol in current Duloxetine, a centrally acting analgesic, in the Victoria, Australia, 2000-09. Injury Prevention 2011; treatment strategies for musculoskeletal pain. treatment of patients with osteoarthritis knee pain: 17: 254-259. Ther Clin Risk Manag 2007; 3: 717-723. a 13-week, randomized, placebo-controlled trial. 39. Large RG, Schug SA. Opioids for chronic pain of 53. Paar WD, Poche S, Gerloff J, Dengler HJ. Pain 2009; 146: 253-260. non-malignant origin – caring or crippling. Health Polymorphic CYP2D6 mediates O-demethylation of 65. Skljarevski V, Desaiah D, Liu-Seifert H, et al. Care Anal 1995; 3: 5-11. the opioid analgesic tramadol. Eur J Clin Pharmacol Efficacy and safety of duloxetine in patients with 40. Royal Australian College of General Practitioner 1997; 53: 235-239. chronic low back pain. Spine 2010; 35: E578-E585. (RACGP). Guidelines for the non-surgical 54. Raffa RB, Buschmann H, Christoph T, et al. 66. McAlindon TE, Bannuru RR, Sullivan MC, et al. management of hip and knee arthritis. Melbourne: Mechanistic and functional differentiation of OARSI guidelines for the non-surgical management RACGP; 2009. tapentadol and tramadol. Expert Opin Pharmacother of knee osteoarthritis. Osteoarthritis Cartilage 41. Jones T, Lookatch S, Grant P, McIntyre J, Moore 2012; 13: 1437-1449. 2014; 22: 363-388. T. Further validation of an opioid risk assessment 55. Pergolizzi JD, Schug SA, Raffa RB, Taylor R. 67. Citrome L, Weiss-Citrome A. Antidepressants tool: the Brief Risk Interview. J Opioid Manag 2014; Tapentadol and dual pain inhibition: a new strategy and the relief of osteoarthritic pain – findings from a 10: 353-364. for pain relief in Australia. Chronic Dis Int 2015; 2: study examining adjunctive duloxetine. Int J Clin 42. Berthelot JM, Darrieutort-Lafitte C, Le Goff B, 1011-1018. Pract 2012; 66: 431-433. Maugars Y. Strong opioids for noncancer pain due to 56. Lange B, Kuperwasser B, Okamoto A, et al. 68. Citrome L, Weiss-Citrome A. A systematic review musculoskeletal diseases: not more effective than Efficacy and safety of tapentadol prolonged release of duloxetine for osteoarthritic pain: what is the acetaminophen or NSAIDs. Joint Bone Spine 2015; for chronic osteoarthritis pain and low back pain. number needed to treat, number needed to harm, 82: 397-401. Adv Ther 2010; 27: 381-399. and likelihood to be helped or harmed? Postgrad 43. Centers For Disease Control and Prevention 57. Riemsma R, Forbes C, Harker J, et al. Med 2012; 124: 83-93. Public Health Service US Department of Health and Systematic review of tapentadol in chronic severe 69. Fox C, Richardson K, Maidment ID, et al. Human Services. Guideline for prescribing opioids pain. Curr Med Res Opin 2011; 27: 1907-1930. Anticholinergic medication use and cognitive for chronic pain. J Pain Palliat Care Pharmacother 58. Butler SF, McNaughton EC, Black RA. impairment in the older population: the medical 2016; 30: 138-140. Tapentadol abuse potential: a postmarketing research council cognitive function and ageing 44. Webster L, St Marie B, McCarberg B, Passik SD, evaluation using a sample of individuals evaluated study. J Am Geriatr Soc 2011; 59: 1477-1483. Panchal SJ, Voth E. Current status and evolving role for substance abuse treatment. Pain Med 2015; 70. Stahl SM, Porreca F, Taylor CP, Cheung R, of abuse-deterrent opioids in managing patients with 16: 119-130. Thorpe AJ, Clair A. The diverse therapeutic actions chronic pain. J Opioid Manag 2011; 7: 235-245. 59. Jordan KM, Arden NK, Doherty M, et al. EULAR of pregabalin: is a single mechanism responsible for 45. Davis MP. Twelve reasons for considering recommendations 2003: an evidence based several pharmacological activities? Trends buprenorphine as a frontline analgesic in the manage­ approach to the management of knee osteoarthritis: Pharmacol Sci 2013; 34: 332-339. ment of pain. J Support Oncol 2012; 10: 209-219. report of a Task Force of the Standing Committee for 71. Uceyler N, Sommer C, Walitt B, Hauser W. 46. Pergolizzi J, Aloisi AM, Dahan A, et al. Current International Clinical Studies Including Therapeutic Anticonvulsants for fibromyalgia. Cochrane knowledge of buprenorphine and its unique pharma­ Trials (ESCISIT). Ann Rheum Dis 2003; 62: Database Syst Rev 2013; (10): CD010782. cological profile. Pain Pract 2010; 10: 428-450. 1145-1155. 72. Ohtori S, Inoue G, Orita S, et al. Efficacy of 47. Serpell M, Tripathi S, Scherzinger S, Rojas- 60. Bruyere O, Altman RD, Reginster JY. Efficacy combination of meloxicam and pregabalin for pain Farreras S, Oksche A, Wilson M. Assessment of and safety of glucosamine sulfate in the in knee osteoarthritis. Yonsei Med J 2013; 54: transdermal buprenorphine patches for the management of osteoarthritis: evidence from 1253-1258. treatment of chronic pain in a UK observational real-life setting trials and surveys. Semin Arthritis 73. Leung L. From ladder to platform: a new concept study. Patient 2016; 9: 35-46. Rheum 2016; 45(4 Suppl): S12-S17. for pain management. J Prim Health Care 2012; 4: 48. Leng X, Li Z, Lv H, et al. Effectiveness and safety 61. Bruyere O, Cooper C, Pelletier JP, et al. A 254-258. of transdermal buprenorphine versus sustained- consensus statement on the European Society for 74. Bruyere O, Cooper C, Pelletier JP, et al. An release tramadol in patients with moderate to severe Clinical and Economic Aspects of Osteoporosis and algorithm recommendation for the management of musculoskeletal pain: an 8-week, randomized, Osteoarthritis (ESCEO) algorithm for the knee osteoarthritis in Europe and internationally: a double-blind, double-dummy, multicenter, active- management of knee osteoarthritis - from report from a task force of the European Society for controlled, noninferiority study. Clin J Pain 2015; evidence-based medicine to the real-life setting. Clinical and Economic Aspects of Osteoporosis and 31: 612-620. Semin Arthritis Rheum 2016; 45(4 Suppl): Osteoarthritis (ESCEO). Semin Arthritis Rheum 49. Bohme K, Heckes B, Thomitzek K. [Application S3-S11. 2014; 44: 253-263. of a seven-day buprenorphine transdermal patch in 62. Niesters M, Proto PL, Aarts L, Sarton EY, Drewes multimorbid patients on long-term ibuprofen or AM, Dahan A. Tapentadol potentiates descending COMPETING INTERESTS: Professor Schug: None. diclofenac]. MMW Fortschr Med 2011; 152(Suppl pain inhibition in chronic pain patients with diabetic The Anaesthesiology Unit of the University of 4): 125-132. polyneuropathy. Br J Anaesth 2014; 113: 148-156. Western Australia, which Professor Schug chairs, 50. Grond S, Sablotzki A. Clinical pharmacology of 63. Finnerup NB, Attal N, Haroutounian S, et al. has received research funding, consultation fees, travel grants and lecture honoraria from Pfizer tramadol. Clin Pharmacokinet 2004; 43: 879-923. Pharmacotherapy for neuropathic pain in adults: a Pharmaceuticals, bioCSL, Seqirus, iX Biopharma 51. Cepeda MS, Camargo F, Zea C, Valencia L. systematic review and meta-analysis. Lancet Neurol and Mundipharma in the past 36 months. Tramadol for osteoarthritis: a systematic review and 2015; 14: 162-173. Dr Mohd Arshad: None.

22 MedicineToday ❙ Conventional and Atypical Opioids Supplement SEPTEMBER 2018

Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 PEER REVIEWED FEATURE Tapering off opioid analgesia APO DEMIRKOL MD, MSc, MMed(PainMgt), PhD, FAFPHM, FAChAM Opioids are being increasingly used for treating chronic noncancer pain but adverse events outweigh the benefits of long-term opioid KEY POINTS treatment in these patients. As abrupt cessation of opioid analgesia • The long-term use of opioids for can lead to unpleasant withdrawal symptoms, tapering off opioid analgesia in patients with chronic therapy is the preferred strategy. noncancer pain is associated with health and social problems. he past 20 years have seen an unprec- ­Australia, leading to aggressive marketing • Ceasing opioids abruptly after edented expansion in the use of strategies. These strategies potentially prolonged use may cause withdrawal opioid analgesics in Australia, with contribute to the overuse of opioid anal- symptoms. opioid dispensing episodes increas- gesics for treating chronic noncancer pain • Tapering opioids may improve mood Ting by at least 15-fold.1 One of the most in the time-constrained setting of general and function as well as pain outcomes. important changes in clinical practice during practice, where prescribing a pain killer • A structured tapering program can this period has been the long-term use of for a pain problem may be the expected prevent an unpleasant withdrawal opioid analgesics in treating chronic non- clinical outcome for all involved. It is also experience for the patient. cancer pain. Although the efficacy of opioids important to acknowledge that both for short-term pain relief from acute pain undergraduate medical training curricula Indications for tapering conditions and the necessity of their regular and vocational GP training curricula in There are many valid reasons to consider use in the treatment of cancer pain has been Australia lack a focused pain management tapering a patient’s opioid analgesics, well established, there is insufficient evidence component. including the following: for the long-term benefits of opioid analgesia There is a consensus that adverse events • the patient may decide that they do in the treatment of chronic noncancer pain. outweigh the benefits of long-term opioid not want to be taking any medication Almost half of the opioids prescribed in treatment.3 Misuse of, dependence on and • the side effects of an opioid general practice are for chronic noncancer addiction to these medications present an medication may be intolerable (Box 2) pain.2 Increased patient awareness of and alarming public health problem in Aus- • despite regular dose increases, opioids demand for the right to pain relief, along with tralia. A major concern is the recent upsurge may not be yielding the desired pain ongoing problems of access to multidiscipli- in serious harms associated with opioids, relief and functional outcomes nary chronic pain management services, may ­particularly the substantial increases in • the patient’s condition may improve be adding to the over-reliance of GPs on opi- ­opioid-related hospitalisations and death to a level where the pain medication is oid analgesia when treating this type of pain. rates.1 Hospitalisations related to pharma- no longer necessary There are almost 250 preparations ceutical opioids now outnumber those • the patient may be misusing the of opioid analgesics on the market in related to use in Australia.1 medication or exhibiting aberrant In patients for whom the long-term use drug-related behaviour.4 of opioid analgesics is problematic, due to An appropriate specialist’s input and MedicineToday 2018; 19(9 Suppl): 23-25 either adverse effects or aberrant behaviour, further attention may be required in plan- First published MEDICINE TODAY 2017; abrupt cessation is not an ideal option ning and conducting the tapering process 18(3 Suppl): 14-16 because of the associated withdrawal symp- in some clinical situations. toms (Box 1). Tapering off these medications • Unstable medical and psychiatric Dr Demirkol is a Senior Staff Specialist at the conditions. Langton Centre, South Eastern Sydney Local is an alternative strategy that can prevent As opioid withdrawal is Health District Drug and Alcohol Services, and the discomfort and complications related to associated with anxiety and insomnia, Prince of Wales Hospital Pain Management Centre, withdrawals. if the patient has a condition that would Sydney; and a Conjoint Associate Professor at the This article provides a practical overview be worsened with anxiety, such as a School of Public Health and Community Medicine, of best practice for tapering opioid therapy poorly-controlled arrhythmia or IMAGE SOURCE/H+5 IMAGE IMAGES/DIOMEDIA.COM © UNSW Sydney, Sydney, NSW. in the general practice setting. untreated mood disorder, it is essential

MedicineToday ❙ Conventional and Atypical Opioids Supplement SEPTEMBER 2018 23

Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 Tapering opioid analgesia continued

1. SIGNS AND SYMPTOMS OF OPIOID • consent for urine drug screening 2. SIDE EFFECTS OF OPIOIDS WITHDRAWAL • possible consequences of not following the treatment agreement. Common Less common • Drug craving • Diaphoresis Before starting tapering, it needs to be • Sedation • Hyperalgesia • Anxiety • Mydriasis clearly emphasised to the patient that reduc- • Dizziness • Delayed gastric • Insomnia • Tremor emptying ing the dose of opioid analgesia will not • Nausea • Abdominal pain • Tachycardia • Vomiting • Hormonal • Vomiting • Piloerection necessarily equate to increased pain and that • Constipation dysfunction • Diarrhoea it will, in effect, lead to improved mood and • Tolerance • Muscle rigidity functioning as well as a reduction in pain • Physical • Myoclonus to deal with these problems first. intensity. The prescriber should establish a dependence • Addiction Concomitant sedative medications. • therapeutic alliance with the patient to • Respiratory It is best to avoid the use of sedatives develop a shared and specific goal. For exam- depression during opioid tapering; however, if ple, a patient may decide to withdraw com- there is a clinical indication for these pletely from opioids by the end of the year. rotation so that a dose review in three to four medications, staged dispensing might The prescriber can advise clinically appro- days is possible for both patient and pre- help reduce the risk of overdose. priate goals. In some cases, the goal might scriber. If prescribers do not feel confident • Pregnancy. Severe, acute opioid be to reduce the dose to a certain level if the about opioid rotation (switching from one withdrawal has been associated with patient cannot completely withdraw from opioid to another), they can contact their premature labour and spontaneous the medication. local pain management centre for further abortion, especially during the first The prescribing of opioid analgesia for a advice. trimester. Specialist advice should be prolonged period (usually more than eight Prescribing scheduled doses is potentially sought or relevant guidelines referred weeks) on a regular basis is regulated by state more helpful for the patient than prescribing to before tapering in pregnant women.5 and territory health authorities in Australia.6 as required, as it provides a structure for the • Polysubstance use or access to opioid It is important that the prescribing doctor reduction. Organising pharmacy dispensing medications from other sources. is familiar with the regulation in their state at frequent intervals, such as once- or twice- These patients are best managed in or territory and that the parameters sur- weekly, will help the patient comply with the consultation with addiction services, rounding prescribing practice are clearly tapering plan. It is important to support the possibly within a substitution treatment discussed with the patient. patient in this by not providing them with framework involving methadone or extra prescriptions without a review if they buprenorphine. An inpatient admission Principles of tapering run out of medication before the scheduled to a residential drug and alcohol facility To improve patient safety and achieve a time. At the review, reasons for the extra use may be warranted if the polysubstance practical positive outcome, consolidating should be explored, and the frequency of use (especially the use of other sedating all opioid analgesia into a single long-acting dispensing might be increased. In this way, agents) is prominent. agent is recommended.5 The main objective patients would have fewer tablets available of tapering is to reduce the dose of medi- to them and, if they did take more than pre- Preparation for tapering cation at an interval that will not cause any scribed, they would not experience major As soon as a valid indication for tapering of withdrawal symptoms. withdrawal by the time of the next scheduled opioid analgesics is established, it is important dispensing. to have a conversation with the patient to Type of opioid, dosing and explain the process and develop a treatment dispensing schedule Taper rate and duration agreement. This agreement could include: Unless there is a contraindication, the RACGP A 10% reduction of daily dose of any opi- • time frame for the agreement guidelines recommend all patients beginning oid every one to two weeks is usually well • goals of the taper opioid tapering be switched to controlled-­ tolerated, with no significant withdrawal. • agreed frequency of dose reduction release morphine tablets.5 For converting any When one-third of the initial daily dose • requirement for obtaining the opioid analgesic dose to the appropriate dose is reached, slow the tapering to half the prescriptions from a single clinician of oral morphine, the general principle is to previous rate to minimise withdrawal- and a named pharmacy calculate the total daily morphine-equivalent related anxiety.7 • scheduled appointments for regular dose by using a conversion table (e.g. see ­opioid The pace of the taper depends on the review calculators in Box 3), then starting at half of patient and the reason for tapering. If the • expected effects of the taper this calculated dose of oral, ­controlled-release patient is experiencing serious opioid-­related • disallowing increasing the medication morphine, with a view to adjusting the dose side effects, a faster taper is necessary. An dose without first discussing it with to avoid withdrawal or sedation. It is impor- even more rapid tapering might be warranted the prescriber tant to choose the timing of this opioid if the patient is refusing to see an addiction

24 MedicineToday ❙ Conventional and Atypical Opioids Supplement SEPTEMBER 2018

Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 specialist after exhibiting ­aberrant behaviour, months has now been accepted as good prac- 3. WEANING OFF OPIOID THERAPY: such as injecting, or breaching the treatment tice.9 Medicare covers 36 urine drug screens USEFUL RESOURCES agreement by obtaining medi­cations from within a period of 12 months if they are used multiple sources. A slower rate of tapering is for monitoring purposes. It is important to Professional resources • Opioid Tapering Calculator advisable for patients who are highly anxious ask for testing of the exact agent used in the (Victoria State Government and about the process and who might have taper, as most pathology services do not NPS MedicineWise) ­psychological dependence on the pain medi­ ­routinely test for synthetic opioids such as –– www2.health.vic.gov.au/Api/down cations, or for those who have significant oxycodone. The expectation is that the urine loadmedia/%7B91501663-EA0B- cardiorespiratory conditions.7 will test positive for the prescribed drug and 4985-B996-74C159487EE3%7D • Opioid Calculator App (FPM; ANZCA) For patients who experience severe with- negative for other opioids. –– http://fpm.anzca.edu.au/front-page- drawal symptoms or a worsening of function Involving allied healthcare professionals, news/free-opioid-calculator-app because of an increase in their pain levels or especially a psychologist, during the taper • A Guide to Deprescribing Opioids deterioration of their mood, it is best to hold is likely to increase the patient’s capacity to (Tenni P, Orlikowski C; Deprescribing the daily dose or increase it to a level at which deal with the negative thoughts and stress Clinical Reference Group; Primary Health Tasmania; 2016) they are comfortable. Slowing down the taper associated with the change in treatment. –– www.primaryhealthtas.com.au/ or lessening the amount of dose reduction Excessive reliance or dependence on medi­ sites/default/files/A%20Guide%20 at each taper might help in this scenario. cation is often a stigmatised disorder to to%20Deprescribing%20Opioids.pdf Clinical reviews before each dose reduction which patients cannot easily admit. It can • Recommendations Regarding the Use ensure safety and help reduce anxiety. If be helpful to listen with empathy and with- of Opioid Analgesics in Patients with Chronic Non-Cancer Pain (FPM; the patient is adherent with the treatment out passing judgement, to acknowledge the ANZCA; 2015) agreement but cannot complete the taper, patient’s difficulty in controlling the medi­ –– http://fpm.anzca.edu.au/ maintaining a lower dose with the same cation use and to encourage their efforts. Documents/PM1-2010.pdf treatment structure may be an option. Finally, it is essential to clearly explain • Quick Reference Recommendations for It is advisable to suggest the option of sub- to the patient, and document in the patient Conduct of an Opioid Trial in Chronic Non-Cancer Pain (FPM; ANZCA; 2015) stitution (also called ‘maintenance’) treatment record, that alongside the reducing dose of –– http://fpm.anzca.edu.au/ as soon as failure to taper opioids or heavy opioids, the patient’s tolerance for opioids Documents/4462_001.pdf 8 reliance on opioid analgesia is observed. will be altered as well. If the patient returns Patient resource As regulation and legislation regarding to taking the initial dose after a period of • Pain and Role of Medications (Pain ­substitution treatment are governed by the reduction, this reduced tolerance makes it Management Network [Agency for states and territories in Australia, it is best to likely that they may experience serious Clinical Information]) –– www.aci.health.nsw.gov.au/ discuss the practicalities of this with a local adverse effects, including opioid overdose chronic-pain/for-everyone/pain- addiction specialist or treatment centre. and respiratory depression. and-role-of-medications The duration of the taper would depend Abbreviations: ANZCA = Australian and New Zealand on the initial dose and the patient’s condition Conclusion College of Anaesthetists; FPM = Faculty of Pain Medicine. and adherence with the plan. It is advisable There are valid reasons to wean patients off 5. Royal Australian College of General Practitioners. to include the intended taper duration in their long-term use of opioid analgesics. Prescribing drugs of dependence in general practice, the initial treatment agreement and revise A structured and well-planned tapering Part A – Clinical governance framework. Melbourne: it if the plan changes. program will improve treatment outcomes RACGP; 2015. Available online at: www.racgp.org.au/ and reduce the complications associated download/Documents/Guidelines/Addictive-drugs/ Addictive-drugs-guide-A.pdf (accessed February 2017). Monitoring MT with opioid withdrawal. 6. Jammal W, Gown G. Opioid prescribing pitfalls: Scheduling frequent visits for the patient, in medicolegal and regulatory issues. Aust Prescr 2015; keeping with the tapering rate and, if possible, References 38: 198-2037 ie 198-203. before each dose reduction (e.g. weekly or 1. Blanch B, Pearson SA, Haber PS. An overview of 7. Suttner J, White Lovett A, Vernachio K. Best fortnightly), will allow the prescribing doctor the patterns of prescription opioid use, costs and practices in tapering methods in patients undergoing opioid therapy. Adv Pharmacol Pharm 2013; 1: 42-57. to monitor the patient’s pain status, with- related harms in Australia. Br J Clin Pharmacol 2014; 78: 1159-1166. 8. Johnson RE, Fudala PJ, Payne R. Buprenorphine: drawal symptoms and benefits of the taper, 2. Harrison CM, Charles J, Henderson J, Britt H. considerations for pain management. J Pain Symptom such as reduced pain and improved mood, Opioid prescribing in Australian general practice. Med J Manage 2005; 29: 297-326. energy level and alertness. These consulta- Aust 2012; 196: 380-381. 9. Starrels JL, Becker WC, Alford DP, Kapoor A, tions should focus on the benefits of the taper, 3. Noble M, Treadwell JR, Tregear SJ, et al. Long-term Williams AR, Turner BJ. Systematic review: treatment agreements and urine drug testing to reduce opioid rather than simply the medication dose and opioid management for chronic noncancer pain. Cochrane Database Syst Rev 2010; (1): CD006605. misuse in patients with chronic pain. Ann Intern Med rate. Using a urine drug screen to assess 4. Cohen ML, Wodak AD. Judicious use of opioids in 2010; 152: 712-720. adherence for every patient who has been chronic non-malignant pain. Med Today 2010; 11(2): taking opioid analgesia for more than three 10-18. COMPETING INTERESTS: None.

MedicineToday ❙ Conventional and Atypical Opioids Supplement SEPTEMBER 2018 25

Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 PEER REVIEWED FEATURE Opioid prescribing in general practice A proposed approach MILTON L. COHEN MD, FRACP, FFPMANZCA; ALEX D. WODAK AM, MB BS, FRACP, FAChAM GPs can prescribe opioids optimally in their practices by following the five principles of opioid prescribing, utilising the five tools for assessment of use and using the five criteria for evaluating outcomes of an opioid trial.

he shared predicament of the patient approach to opioid prescribing for patients with chronic noncancer pain and with chronic noncancer pain. This updated KEY POINTS the primary care physician, both version is presented in the face of the cur- grappling with management of this rent controversy regarding the role of opi- • The complex experience of chronic Tcomplex problem, were discussed in a pre- oids in the management of patients with pain has biological, psychological vious article.1 We acknowledged that apply- chronic noncancer pain, recognising that and social contributions, each of which you need to assess. ing the desired biopsychosocial framework there is weak evidence of effectiveness and Drug therapy for patients with 2 • for assessment requires skill and time, the that harms are not inconsiderable. This chronic noncancer pain is only part latter being at a premium in general practice. article is morally neutral on this issue but of a multifaceted, multi­disciplinary, It was not at all surprising, therefore, that in practical and realistic in its intent. treatment approach. If drugs are practice the management of such patients The framework for the approach pre- needed to treat patients with generally defaults to the use of analgesic sented comprises the five principles pre- chronic noncancer pain, ensure you drugs, frequently opioids. Accordingly, a set viously offered, five tools that may assist also pay attention to psychological of principles were presented that could be assessment and five criteria for evaluating and social stresses. applied for the more judicious use of opioids the outcome of the ongoing trial of opioid • Appreciate that opioid pharma­ in this context. pharmacotherapy in patients with chronic cotherapy for patients with chronic In this article we translate the principles pain (Box 1). noncancer pain is always an ongoing trial of therapy. previously described into a practical Be aware of the regulations Step 1. Comprehensive • regarding opioid prescribing in (‘sociopsychobiomedical’) your jurisdiction and of the ‘rules’ assessment regarding PBS-subsidised opioids. MedicineToday 2018; 19(9 Suppl): 26-32 The experience of chronic pain has social, • Document any opioid trial carefully First published MEDICINE TODAY 2012; psychological and biomedical contribu- and if it is not working start tapering 13(1): 24-32 the dose to zero. If you are not sure Updated September 2018 tions, each of which needs to be assessed. what to do, ask for advice from a colleague experienced in chronic Professor Cohen is a Specialist Pain Medicine ‘Socio-’ (what is happening in pain, a pain specialist, an addiction Physician, St Vincent’s Campus, Sydney. the person’s world) medicine specialist or a psychiatrist. Dr Wodak is Emeritus Consultant, St Vincent’s Assess not only the effects of pain on rela-

Hospital, Sydney, NSW. tionships – family, friends, work and leisure © TODD BUCK ILLUSTRATIONS, INC.

26 MedicineToday ❙ Conventional and Atypical Opioids Supplement SEPTEMBER 2018

Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 1. FRAMEWORK FOR A PRACTICAL 2. PROBLEMATIC OR ABERRANT APPROACH TO OPIOID PRESCRIBING DRUG-TAKING BEHAVIOURS IN CHRONIC NONCANCER PAIN • Overwhelming focus on opioid issues, 5 principles impeding progress with other issues • Comprehensive assessment • Resistance to change in therapy • Poor response to other therapies despite evidence of adverse drug effects • Agreement regarding opioid trial • Aggressive complaining about the • Conduct of opioid trial need for more drugs • Responses to difficulty achieving or • Noncompliance with use instructions, maintaining goals in an opioid trial including nonsanctioned dosage 5 tools escalation • Brief Pain Inventory • Pattern of prescription problems (i.e. • Opioid risk tool (or other instrument) lost, spilled or stolen medications) • Contact numbers for advice regarding • Supplemental opioids (from other prescribing regulations in the providers, emergency departments or different Australian jurisdictions illicit sources) • Opioid contract • Stealing or ‘borrowing’ drugs • Chart of opioid ‘equianalgesic’ doses • Selling prescription drugs • Prescription forgery 5 criteria • Evidence of deterioration in function • Analgesia including family, work and social – but also the influence of other life events, • Activity life ranging from changes within families to • Adverse effects • Concurrent abuse of alcohol or other environmental disasters. • Affect illicit drugs A useful tool to aid this assessment is • Aberrant behaviours • Injecting oral formulations the Brief Pain Inventory (see Toolbox 1). It allows patients to rate their pain on a scale of 0 to 10, where 0 is no pain and 10 is the patient’s condition. Chronic pain is often diagnostic language to use is difficult here. worst pain possible. associated with changes in mood, especially For example, ‘lumbar spondylosis’ is a An important part of this step is to assess depression and anxiety, and with loss of ­statement of age-related anatomical fact the risk of problematic opioid use, by asking self-esteem. Much pain-related behaviour and does not imply either the presence or the following questions: stems from patients’ beliefs regarding diag- mechanism of pain. • Is there a personal or family history nosis and prognosis that are frequently of past or current alcohol or drug catastrophic and incorrect. Much distress Step 2. Adequate trial of other problems? can be alleviated by careful, accurate and reasonable therapies • Is an active or recent psychiatric realistic explanations, often about what is Drug therapy – for symptom control – is disorder present? not wrong. an adjunct to a comprehensive care plan. • Is there evidence of problematic Often that plan will need to include the drug-taking behaviours? (Box 2) ‘-biomedical’ (what is happening help of other health professionals. ‘Positive’ responses here do not neces- to the body) Nondrug treatment options include an sarily preclude a trial of opioid therapy but Try to identify an underlying treatable accurate explanation, especially realistic rather act as an alert to guide monitoring condition, if suspected on the basis of prognostication (there is often no ‘cure’ for of a trial. A useful tool is the opioid risk clinical ‘red-flag’ features (e.g. inflamma- chronic pain) and advice regard­ing nutri- tool (see Toolbox 2).3 tion, infection, neural pathology, neo- tion, exercise, sleep hygiene and the pursuit plasm). However, most chronic pain is not of pleasurable activities. Emphasise the ‘-psycho-’ (what is happening to due to a ‘broken part’ but is more likely to need for daily activity, not rest, and the the person) reflect altered function (in particular important role of pacing to limit fatigue. Assess the impact of pain on the patient’s altered central­ ). This is espe- Consider referral of the patient to appro- daily activities (work and recreation) and cially so for pain experienced in muscu- priate healthcare personnel, if available, for sleep. Explore the role of fatigue in the loskeletal tissues. Finding the correct more intensive exploration of these options.

MedicineToday ❙ Conventional and Atypical Opioids Supplement SEPTEMBER 2018 27

Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 Opioid prescribing in general practice continued

TOOLBOX 1. BRIEF PAIN INVENTORY*

NAME: 6. Please rate your pain by circling the one number that tells how DATE: much pain you have right now. TIME: 0 1 2 3 4 5 6 7 8 9 10 1. Throughout our lives, most of us have had pain from time to No pain Pain as bad as time (such as minor headaches, sprains and toothaches). Have you can imagine you had pain other than these everyday kinds of pain today? 7. What treatments or medications are you receiving for your pain? 1. Yes 2. No

2. On the diagram, shade in the area where you feel pain. Put an X on the area that hurts the most. 8. In the past 24 hours, how much relief have pain treatments or medications provided? Please circle the one percentage that shows how much relief you have received. Left Right Left 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 10% No relief Complete relief

9. Circle the one number that describes how, during the past 24 hours, pain has interfered with your: A. General activity 0 1 2 3 4 5 6 7 8 9 10 Does not interfere Completely interferes

B. Mood 0 1 2 3 4 5 6 7 8 9 10 Does not interfere Completely interferes

C. Walking ability 0 1 2 3 4 5 6 7 8 9 10 3. Please rate your pain by circling the one number that best Does not interfere Completely interferes describes your pain at its worst in the past 24 hours. D. Normal work (includes both work outside the home and 0 1 2 3 4 5 6 7 8 9 10 housework) No pain Pain as bad as you can imagine 0 1 2 3 4 5 6 7 8 9 10 Does not interfere Completely interferes 4. Please rate your pain by circling the one number that best describes your pain at its least in the past 24 hours. E. Relations with other people 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 No pain Pain as bad as Does not interfere Completely interferes you can imagine

5. Please rate your pain by circling the one number that best F. Sleep describes your pain on average. 0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10 Does not interfere Completely interferes No pain Pain as bad as you can imagine G. Enjoyment of life 0 1 2 3 4 5 6 7 8 9 10

* Reproduced with permission from Dr Charles S. Cleeland (1991). Does not interfere Completely interferes

28 MedicineToday ❙ Conventional and Atypical Opioids Supplement SEPTEMBER 2018

Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 As symptom control is important, ­consider the role of nonopioid analgesic TOOLBOX 2. OPIOID RISK TOOL*2 ­medications, especially paracetamol. So-called adjuvant analgesics include Risk factor Male (score) Female (score) ­tricyclic antidepressants, such as Family history (parents and siblings) ­a­mi­­trip­­tyline and (both used • Alcohol abuse (3) (1) off label), serotonin and noradrenaline • Illegal drug use (3) (2) • Prescription drug abuse (4) (4) reuptake inhibitors, such as duloxetine and venlafaxine (both used off label), and Personal history anticonvulsants, such as gabapentin and • Alcohol abuse (3) (3) pregabalin (both indicated for the treat- • Illegal drug use (4) (4) ment of neuropathic pain). These analge- • Prescription drug abuse (5) (5) sics may have a role but may be limited by Mental health cognitive side effects, drowsiness or, in • Diagnosis of ADD, OCD, bipolar disorder (2) (2) some cases, high cost. or schizophrenia In this context, invasive therapies, rang- • Diagnosis of depression (1) (1) ing from injections to implants, may not Other be considered ‘reasonable’, especially when • Age 16 to 45 years (1) (1) there is no local ‘broken part’ to be fixed. • History of preadolescent sexual abuse (0) (3) Opioid use should be considered before Total score ______invasive options. Total score risk category: 0 to 3 = Low risk: 6% chance of developing problematic behaviours. Step 3. Agreement regarding 4 to 7 = Moderate risk: 28% chance of developing problematic behaviours. opioid trial ≥8 = High risk: more than 90% chance of developing problematic behaviours.

Opioid pharmacotherapy for patients with Abbreviations: ADD = attention deficit disorder; OCD = obsessive compulsive disorder. chronic pain is an ongoing trial, repeatedly *Adapted with permission from Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: addressing the question, ‘Is this patient’s preliminary validation of the opioid risk tool. Pain Med 2005; 6: 432-442. predicament opioid-responsive?’ Such a trial is always a part of a mul- TOOLBOX 3. CONTACT NUMBERS FOR ADVICE REGARDING OPIOID timodal treatment plan. Given that opi- oids are controlled drugs, a ‘contract’ Jurisdiction Agency Telephone Fax between prescriber and patient should be ACT Pharmaceutical Services, ACT Health 02 6205 0998 02 6205 0997 explicit, with ongoing prescription depending on evidence of worthwhile NSW Pharmaceutical Services Branch, 02 9879 5239 02 9859 5175 ongoing benefit and minimal harm. The NSW Ministry of Health agreement extends to: NT Poisons Control, 08 8922 7341 08 8922 7200 • identifying realistic activity goals, Department of Health and Community tailored to the individual patient, Services that emphasise improved function, QLD Drugs of Dependence Unit, 07 3328 9890 07 3328 9821 not just less discomfort Queensland Health • one prescriber (and deputy) and a SA Drugs of Dependence Unit, 08 8274 3434 08 8274 3433 single pharmacy dispensing Pharmaceutical Services, according to risk assessment, with no SA Health early repeat prescriptions or loss replacements TAS Pharmaceutical Services 03 6233 2064 03 6233 3904 Branch, Department of Health • setting review intervals, perhaps and Human Services weekly for the initial trial and up to third-monthly for stable VIC Drugs and Poisons Regulation, 1300 364 545 1300 360 830 Department of Health patients • tapering dose to termination of the WA Pharmaceutical Services, 08 9222 4424 08 9222 2463 Department of Health opioid trial if treatment goals

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(including review appointments) TOOLBOX 4. EXAMPLE OF A TREATMENT CONTRACT FOR THE USE OF OPIOIDS FOR THE MANAGEMENT OF CHRONIC PAIN* are not met, there are serious adverse outcomes or there is evidence of misuse, especially Patient name: unsanc­t­ioned use such as self- Address: injection, stock­piling, selling or Date of birth: giving drugs to others • including an option for random drug I, [Add name here], understand that opioid painkillers are being prescribed to me in an monitoring, such as by urine drug attempt to improve my level of functioning and reduce my pain intensity. My medical screen or pill counts. practitioner and I agree to the following conditions regarding my treatment and the Prescribers should be familiar with the prescribing of opioid medications for my pain. We have discussed that strong opioid (morphine-like) painkillers may be only partially helpful in achieving this goal and on regulatory requirements in the state or occasion will not help at all. I understand that painkillers are only one part of the ­territory jurisdiction of their practice (see management of my chronic pain. Toolbox 3 for contact numbers for Phar- 1. My medical practitioner is responsible for prescribing a safe and effective dose maceutical Services Branches in each juris- of opioids. I will not use opioids other than at the dose prescribed and I will discuss diction in Australia). Some jurisdictions any changes in my dose with my medical practitioner. may require an opioid contract to be signed 2. I am responsible for the security of my opioid medicine. Lost, misplaced or stolen by the patient and medical practitioner (see prescriptions or medicine will not be replaced. Toolbox 4). All prescribers should note the 3. I will only obtain opioid medications from the medical practitioner who signs this importance of attention to documentation, contract, or other doctors in the same practice authorised to prescribe to me. regulation and adherence to advice from I understand that no early prescriptions will be provided. the Pharmaceutical Services Branch in 4. Although most people do not have any serious problems with this type of medicine their jurisdiction of practice. when used as directed, there can be side effects. My medical practitioner will let me know what these are and I will tell him or her if I experience them. Step 4. Conduct of an opioid trial 5. I am aware that my medical practitioner is required to gain authorisation from the A trial of opioid analgesic therapy requires Department of Health for continued prescription of these medications. goal-setting, explicit agreements, skilled titration of dose and regular monitoring of 6. I agree to tell my medical practitioner if I have ever been dependant on alcohol or drugs, or if I have ever been involved in illegal activity related to any drugs including the 5A criteria. prescription medicines. I am aware that providing my medicine to other people is The pharmacological principle of an illegal and could be dangerous to them. opioid trial is to use long-acting (long half- 7. My medical practitioner respects my right to participate in decisions about my life) oral or transdermal opioid pre­ pain management and will explain the risks, benefits and side effects of any parations, dosing according to age (see treatment. Table). The starting dose should be low if 8. My medical practitioner and I will work together to improve my level of functioning the patient is opioid naïve, of the order of and reduce my pain. 10 mg daily oral morphine equivalent. If 9. I understand that my medical practitioner may stop prescribing opioids or change the patient is already taking an immediate-­ the treatment plan if my level of activity has not improved or I do not show a release opioid (e.g. codeine, morphine or significant reduction in pain intensity, or if I fail to comply with any of the conditions oxycodone) or tramadol, calculate the listed above. daily dose and use the equianalgesic chart (see Toolbox 5) to convert it to an approx- Patient signature: imate daily equivalent of a long-acting Name: oral or transdermal preparation. Date: Regularly reassess the patient and doc- Medical practitioner: ument details, according to the 5A criteria, which are: Provider number: • analgesia Date: • activity

* Adapted from the Drug and Alcohol Office/Pharmaceutical Services Branch, WA Department of Health. • adverse effects • affect • aberrant behaviour.

30 MedicineToday ❙ Conventional and Atypical Opioids Supplement SEPTEMBER 2018

Permission granted by Medicine Today for Pain Australia to circulate this supplement © Medicine Today 2018 TABLE. SUSTAINED-RELEASE OR LONG-ACTING OPIOID PREPARATIONS FOR USE IN TOOLBOX 5. APPROXIMATE OPIOID PATIENTS WITH CHRONIC NONCANCER PAIN DOSES EQUIANALGESIC TO ORAL MORPHINE 30 MG Generic name Seek advice if dose exceeds

Oral opioid agonists Oral

Hydromorphone 12 mg daily • Tapentadol 75 mg • Tramadol 150 mg Methadone 20 mg daily • Codeine 180 mg Morphine 60 mg daily • 130 mg • Methadone 10 mg* Oxycodone 40 mg daily • Oxycodone 20 mg Oral opioid-like activity • Hydromorphone 4 mg Tapentadol 150 mg daily Sublingual • Buprenorphine 0.4 mg Tramadol 300 mg daily Parenteral Transdermal opioids • Tramadol 100 mg

Buprenorphine 30 mcg/h weekly • Morphine 10 mg • Hydromorphone 1.5 mg Fentanyl 25 mcg/h every three days Transdermal • Buprenorphine 20 mcg/h Whether initiating or continuing ther- that an apparent opioid requirement • Fentanyl about 12 mcg/h apy, review weekly initially, then accord- approaching this should trigger a com- * Morphine:methadone 3:1 for morphine less than ing to achievement of goals. Titration of prehensive reassessment of the patient. If 100 mg daily only. dose according to the 5A assessment over tapering of opioid therapy is required, the four to six weeks should allow the funda- suggested rate is to reduce the daily dose framework. In patients with established mental question, ‘Is this person’s predic- by 10% each week. chronic pain, it is unlikely that there will ament opioid-responsive?’, to be answered. If in doubt about any aspect of the opioid be a change in the underlying disease A decision can then be made to continue trial, enlist the opinion of a colleague or a state, although alertness to clinical fea- maintenance therapy, subject to ongoing specialist pain or addiction medicine phy- tures suggesting such change is impor- satisfactory assessments of the 5As, test sician. For regulatory purposes, this should tant. It is more likely that difficulty in the effects of dose reduction or taper to be done at least annually in any case. achieving the goals reflects a change in withdrawal. the patient’s psychosocial situation or a The main focus of the opioid trial Step 5. Response to difficulty response to other life stressors. should be on improved function – physical, achieving or maintaining goals In this situation, a new ‘contract’ can be cognitive and social. How active does the in an opioid trial, including negotiated, perhaps with revised goals and patient want to be? Is the patient able to demands for an increase in dose review plans, provided that the fundamental achieve this level of activity? Is that level Difficulty achieving or maintaining the goals question, ‘Is this person’s predicament of activity appropriate under the circum- of an opioid trial should trigger compre­hen­ opioid-responsive?’, has a ­positive answer. stances? Given the variable course of sive reassessment of the patient (steps 1 to 4), If there is evidence of increased function, chronic pain, it may well be that over time which may then require referral. it is probable that the trial is positive but opioid requirements fluctuate, not neces- The two main problems that may be the patient needs to observe better ‘pacing’ sarily upward. encountered in an opioid trial are: of activity. If relative under-dosage is sus- Try to tailor the drug regimen to indi- • a claim that there has been no pected, a trial of increased dose can be vidual patient needs, such as taking the change in pain despite evidence of considered, again to be evaluated using the drug at night only to ameliorate sleep, or increased function 5A criteria. If adverse effects of the opioid asymmetrically varying the dose during • evidence of unsanctioned use of are a problem but the trial is otherwise the day according to required or anti­ the drug. positive, changing to another opioid could cipated activity levels. Limit the dose to a However, the same principles apply, be considered (see Toolbox 5). However, if maximum of 100 mg daily oral morphine starting with repeat assessment, especially there is evidence of unsanctioned opioid equivalent (see Toolbox 5). It is suggested at the ‘social-’ and ‘-psycho-’ levels of the use (Box 2), taper the opioid to withdrawal

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Pain management in the behaviors in opioid-treated patients: preliminary and refer the patient to a specialist pain or validation of the opioid risk tool. Pain Med 2005; addiction medicine physician. opioid-dependent (‘addicted’) 6: 432-442. patient What about the ‘inherited’ Many people on opioid-substitution treat- patient? ment programs (with methadone or Further reading The ‘inherited’ patient, especially one taking buprenorphine) have concurrent chronic Chou R, Fanciullo GJ, Fine PG, et al; American Pain Society-American Academy of Pain Medicine more than 100 mg/day oral mor­phine pain. This is likely to be as difficult to treat Opioids Guidelines Panel. Clinical guidelines equivalent, is a common situation. The as in other patients and only partly respon- for the use of chronic opioid therapy in same principles apply as for patients under- sive to opioid treatment. chronic noncancer pain. J Pain 2009; 10: going an opioid trial, namely: The request for an increased opioid dose 113-130. • perform a sociopsychobiomedical to reduce the severity of pain can be con- NPS MedicineWise. Chronic pain. 2015. Available reassessment (over time) sidered on a trial basis but any change to a online at: www.nps.org.au/medical-info/clinical- • establish new contract with set goals ‘preferred’ drug should be resisted. If pos- topics/chronic-pain. • carry out regular 5A criteria sible try to manage chronic pain in patients Royal Australian College of General Practitioners. assessment on opioid-substitution treatment by Prescribing drugs of dependence in general • refer patient if in doubt. increasing the dose of methadone or practice, Part C2: the role of opioids in pain When conducting an opioid trial in buprenorphine rather than by introducing management. Melbourne: RACGP; 2017. Available these patients: another opioid. online at: www.racgp.org.au/your-practice/ • convert, in stages, all current opioids Otherwise consider referring the guidelines/drugs-of-dependence-c. that the patient is taking to one form patient for specialist advice. An excep- Royal Australasian College of Physicians. only of nonparenteral opioid. tion might be presentation with an epi- Prescription opioid policy: improving management of chronic non-malignant pain and (Transdermal fentanyl is not sode of acute nociception, such as bony prevention of problems associated with recommended as rapid tolerance trauma, in which case a temporary prescription opioid use. Sydney: Royal appears to be a problem and dose increase in dosage of the current opioid Australasian College of Physicians; 2009. titration is difficult.) For example, could be considered. Available online at: www.racp.edu.au/docs/ 80% current opioids and 20% new default-source/advocacy-library/prescription- opioid for a week, then 60% current Conclusion opioid-policy-improving-management-of- opioids and 40% new opioid for a The cornerstones of quality use of opioids chronic-non-malignant-pain-and-prevention- similar period, then 40% current in the management of patients with of-problems-associated-with-prescription- opioids and 60% new opioid, etc to chronic noncancer pain are: opioid-use.pdf. full conversion • comprehensive Faculty of Pain Medicine, Australian and New • the patient may find that the current sociopsychobiomedical Zealand College of Anaesthetists. preferred opioid has high ‘likeability’. In assessment Recommendations regarding the use of opioid analgesics in patients with chronic non-cancer that case, conversion may take several • ongoing trial of opioid pain. Professional Document PM1, June 2015. months. Be prepared to slightly increase responsiveness using long-acting Available online at: http://fpm.anzca.edu.au/ the dose of the new main opioid oral or transdermal preparations documents/pm1-2010.pdf • seek to establish the lowest dose of • regular 5A re-evaluation National Academies of Sciences, Engineering and the one opioid species that • careful documentation of goals, Medicine. Pain management and the opioid facilitates the patient maintaining decisions and advice received. MT epidemic: balancing societal and individual activity in reasonable comfort with benefits and risks of prescription opioid use. minimal side effects. Each decrement References Washington DC: The National Academies Press; could be 10% of the current daily 2017. 1. Cohen ML, Wodak AD. The judicious use of Schug SA, Sekandarzad MW. Use of opioids in dose. It may not matter if the opioid opioids in managing chronic noncancer pain. Med chronic noncancer pain. Med Today 2018; 19(9 cannot be withdrawn completely, Today 2010; 11(2): 10-18. Suppl): 12-15. provided that the patient is able to be 2. Chou R, Turner JA, Devine EB, et al. The as active as he or she wishes to be effectiveness and risks of long-term opioid • involve the patient in decision therapy for chronic pain: a systematic review for a COMPETING INTERESTS: Professor Cohen has making about the transition unless it National Institutes of Health Pathways to received fees historically from Mundipharma for preparation and presentation of educational Prevention Workshop. Ann Intern Med 2015; 162: becomes clear that the patient is material. Dr Wodak has received fees historically sabotaging that process. In that case, the 276-286. from Mundi­pharma for preparation and patient should be referred to a specialist. 3. Webster LR, Webster RM. Predicting aberrant presentation of educational material.

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