Hrev_master Abstract Blunt chest trauma with isolated or multiple rib fractures con- stitutes a common presentation in Emergency Department (ED), particularly in elderly people. Rib fractures in the elderly create short- and long-term disabilities with a dramatic impact. Pain man- agement in the elderly could be problematic due to non-steroidal anti-inflammatory drugs (NSAIDs) contraindication or interaction with other drugs. We performed this retrospective study collecting and retrieving all patients aged 65 or older, with a diagnosis of rib(s) fracture(s) during an 18-month period. We analyzed the dif- ferent treatments chosen, and divided them into subgroups: oxy- codone-naloxone, and other treatments (also divided in: codeine- acetaminophen; NSAID or Acetaminophen; Tramadol or Tapentadol). A total of 475 elderly patients (aged 65 and older) with single or multiple rib fractures were evaluated in our ED in 18 months: of these 410 patients were considered eligible, with a mean age of 79.28 years (standard deviation 7.83). 185 were male and 225 were female. Our study confirms the efficacy and tolera- bility of fixed association of oxycodone and naloxone. This asso- ciation determined the highest and fastest reduction on Numeric Pain Scale reported by patients and is significantly better than other drugs in oral administration. Introduction Blunt chest trauma with isolated or multiple rib fractures con- stitutes a common presentation in Emergency Department (ED), particularly in elderly people.1 Rib fractures in the elderly create short- and long-term disabilities with a dramatic impact on the patient’s quality of life.2 Rib fractures are considered among the most painful injuries in thoracic blunt trauma,2 but pain manage- ment in the elderly could be problematic due to non-steroidal anti- inflammatory drugs (NSAIDs) contraindication or interaction with other drugs:3 further, comorbidities, frailty, cognitive dysfunction, and chronic illness require additional attention in the choice of drugs and doses.4,5 Finally, acetaminophen could be ineffective in most severe pain, and opioids are considered the elective pharma- cological treatment in these cases6,7 although recent reports have highlighted the promising results given by regional anesthesia.8,9 Oxycodone is a semisynthetic, strong opioid analgesic with high oral bioavailability and proven efficacy in treatment of severe pain.10-16 The side effects of opioid use are well known, and consti- pation is the most frequently reported especially in the elderly:15-17 constipation naturally increases with age,14,18-20 and opioid treat- ments could potentially increase this aspect: in many cases, it may induce patients to reduce or discontinue their opioid therapy, deter- mining oligoanalgesia.21,22 Naloxone is an opioid antagonist with an oral bioavailability of 2% due to a strong first-pass hepatic metabolism:23 when given by mouth, the naloxone systemic side effects are negligible, and it exerts its action on gut opioid recep- tors with a higher affinity than oxycodone preventing oxycodone from binding to these receptors.24,25 So, the association between oxycodone and naloxone in a fixed ratio of 2:1 can reduce the prevalence of constipation or improve bowel function in patients with preexistent constipation without affecting analgesic effects.18,23,25,26 We decided to evaluate the analgesic efficacy of the association of oxycodone-naloxone in pain management of elderly patients with isolated or multiple rib fractures and to investigate the prevalence of opioids side effects. Emergency Care Journal 2019; volume 15:8119 Correspondence: Alessandro Riccardi, Emergency Department, San Paolo Hospital, Via Genova, 17100 Savona, Italy. Tel.: +39.019.8404963. E-mail: dottriccardi@gmail.com Key words: Pain management; Oxycodone; Opiates; Blunt chest trauma. Contributions: AR conducted the study, collected the data, performed the statical analys, and wrote the introduction and discussion section; BS collected the data, reviewed the data and wrote the materials section; PM collected and reviewed the data, and reviewed references; ML col- lected the data and wrote the results section; VG collected and reviewed the data and reviewed references; RL coordinated the work and co- wrote all sections. Conflict of interest: the authors declare no potential conflict of interest. Funding: none. Received for publication: 19 February 2019. Revision received: 29 March 2019. Accepted for publication: 24 May 2019. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2019 Licensee PAGEPress, Italy Emergency Care Journal 2019; 15:8119 doi:10.4081/ecj.2019.8119 [Emergency Care Journal 2019; 15:8119] [page 79] Efficacy and tolerability of fixed association of oxycodone and naloxone in elderly patients with ribs fracture: An 18-month retrospective study Alessandro Riccardi, Beatrice Spinola, Pierangela Minuto, Marco Licenziato, Valeria Ghiglione, Roberto Lerza Emergency Department, San Paolo Hospital, Savona, Italy Non -co mmerc ial us e o nly [page 80] [Emergency Care Journal 2019; 15:8119] Materials and Methods Study setting and design We performed this retrospective study in our ED (city hospital, approx. 55,000 access/year, San Paolo Hospital, Savona, Italy), collecting and retrieving all patients aged 65 or older, with a diag- nosis of rib(s) fracture(s) (using specific query), during an 18- month period (June 1st, 2017-December 31st, 2018). Baseline data included demographics (age, gender) as well number of rib frac- tures were collected. We reviewed clinical records by physicians and nurses, and recorded data about pain evaluation and re-evalu- ation, and constipation. We excluded such patients with incomplete or incorrect clinical records. Each patient received a first pain measurement using a verbal Numeric Pain Scale (NPS): subjects were asked to define their pain score using a verbal numeric rating scale, in which 0 is defined as no pain and 10 is defined as worst pain imaginable. Pain scores were measured at baseline. The physician decided on analgesia by oral route based on personal opinion, and re-evaluated NPS at 90 minutes. We analyzed the different treatments chosen, and divided them into subgroups: oxycodone-naloxone, and other treatments (also divided in: codeine-acetaminophen; NSAID or Acetaminophen; Tramadol or Tapentadol). Table 1 summarizes dosing information. According to clinical conditions (i.e., number of rib fractures, co-morbidities) physicians decided on discharge, or admission to hospital (mostly in our Emergency Medicine Ward): in these patients, we evaluated also NPS at 24 hours after admission (in the admitted patients the NPS was furtherly evaluated at 24 hours according to our internal protocol adopted in all patients with mod- erate or severe pain). In case of insufficient analgesia, the initial daily dose was increased. Changes in cognitive state, constipation, and other adverse events were assessed, like nausea. Data analysis In the descriptive analysis, main trends and dispersion meas- urements (mean and standard deviations) were used for NPS. The significance of difference between different groups of pain treat- ment was evaluated by the Student’s t-test. The correlation between parameters was calculated with Pearson Coefficient and Linear Regression. Data were analyzed using Microsoft Excel 2010. This study was authorized by the medical direction of our hospital and patients were informed and signed their consent to their data collection. Article Table 1. Different analgesic treatments used and their dosing. Drug Starting dose Oxycodone – Naloxone group Oxycodone-Naloxone 5 mg-2.5 mg p.o. Codeine-Acetaminophen group Codeine-Acetaminophen 30 mg-500 mg p.o. NSAIDs or Acetaminophen group Acetaminophen 1000 mg p.o. Ketoprofen 80 mg p.o. Ibuprofen 600 mg p.o. Tramadol or Tapentadol group Tramadol 50 mg p.o. Tapentadol 50 mg p.o. NSAIDs, non-steroidal anti-inflammatory drugs; p.o., per os. Table 2. Demographic characteristics of patients and response to different treatment options. Oxycodone-Naloxone Other treatment Codeine-Acetaminophen NSAIDs or Acetominophen Tapentadol or Tramadol (n=222) (n=189) (n=123) (n=25) (n=12) NPS before (Mean) 8.315315315 7.542553191 7.650406504 6.56 8.25 NPS 90’ (Mean) 6.617117117 6.207446809 6.154471545 5.48 6.833333333 NPS 24h (Mean) 4.972972973 5.972972973 5.837837838 5.875 6 Mean age 80.61 (65-101) 77.7 (65-95) 78.11 (65-95) 74.56 (65-91) 79.17 (65-90) SD 7.237 SD 8222 SD 8.071 SD 8.879 SD 9.134 Number of ribs 2.02 (1-10) 2.07 (1-14) 1.94 (1-14) 1.76 (1-4) 2.72 (1-5) fractures (Mean) SD 1.223 SD 1.554 SD 1.252 SD 0.95 SD 1.42 NSAIDs, non-steroidal anti-inflammatory drugs; NPS, Numeric Pain Scale; SD, standard deviation. Figure 1. Analgesic effect on Numeric Pain Scale reduction for different treatments used. NPS, Numeric Pain Scale; NSAID, non-steroidal anti-inflammatory drug. Non -co mmerc ial us e o nly [Emergency Care Journal 2019; 15:8119] [page 81] Results and Discussion A total of 475 elderly patients (aged 65 and older) with single or multiple rib fractures were evaluated in our ED in 18 months: of these, 65 patients were excluded for incomplete clinical informa- tion. 410 patients were considered eligible, with a mean age of 79.28 years (standard deviation 7.83). 185 were male and 225 were female. 222 patients were treated with oxycodone and naloxone in a fixed ratio of 2:1, at initial dose of 5 mg-2.5 mg p.o. bid, and 63 patients (28%) needed an increased dose of 10 mg-5 mg at the 24- hour evaluation. 76 patients were admitted to hospital (34.23%). 189 patients were treated with other drugs, and 81 patients (42.85%) required an implementation of analgesia. In these group, 76 patients (40.21%) were admitted. In the Other treatment group, 123 were treated with codeine-acetaminophen association, and 37 were admitted (30.01%), 25 patients were treated with NSAIDs or acetaminophen, 10 were admitted (40%), and 12 patients were treated with tapentadol or tramadol, and all of them were admitted (Table 2). We did not find any significant correlation between the inten- sity of pain and the number of rib fractures, both in the group of patients treated with oxycodone-naloxone (mean rib fractures 2.02, mean NPS at arrival 8.32, Pearson coefficient -0.12, R2 0.0085) and in the group of patients treated with other drugs (mean rib frac- tures 2.07, mean NPS at arrival 7.54, Pearson coefficient 0.54, R2 0.2917). The treatment chosen seemed appropriate, according to the mean NPS at arrival, highest in the group of patients treated with opiates (8.31 in the oxycodone-naloxone group, 8.25 in the tapen- tadol or tramadol group), and lower in patients treated with aceta- minophen or NSAIDs (6.56), but in this latter group we observed a slight reduction in NPS after administration (5.48), followed by an increased NPS at 24h (5.87). In the other groups, the NPS decreased after administration and at 24 hours, with the highest reduction in the oxycodone-naloxone group (P<0.01; Figure 1 and Table 3). The association oxycodone-naloxone was well tolerated: we found drowsiness in 10 patients (4.5%), and constipation in 18 patients (8.1%), mostly pre-existent: we observed these symptoms in the 76 patients admitted in hospital (mean admission period of 4 days, range 2-12 days). The constipation did not worsen in anyone and improved in 4 patients. Nausea was very rare, observed in only 2 patients (0.9%), but we did not observe any vomiting; 1 of these patients decided to switch to other treatment for persistent nausea (0.45%). Conclusions Our study confirms the efficacy and tolerability of fixed asso- ciation of oxycodone and naloxone. This association determined the highest and fastest reduction on NPS reported by patients and is significantly better than other drugs in oral administration. When physicians decided to administer NSAIDs or Acetaminophen, due to a lower NPS value reported by patients, we demonstrated a slight increase in NPS at 24 hours, after an initial reduction, and these data confirm that such analgesic could be inappropriate for treatment of a painful condition like rib fractures.2,3 The conse- quences of oligoanalgesia in the elderly are well-known and docu- mented,21,22 and opiophobia (especially in older patients) lead to over-prescription of NSAIDs,6 even when they are contraindicated or ineffective,3-5 with increased renal and gastrointestinal toxicity.27 Acetaminophen has been recommended by most societies and by the World Health Organization as the first-line agent in the treat- ment of mild-to-moderate pain, given its tolerability, nevertheless its poor analgesic efficacy in severe pain limits its utilization.28 The efficacy of oxycodone-naloxone are well documented, even in eld- erly people.23,24 Our study confirms also the good tolerability of the association of oxycodone-naloxone, as seen in literature:16,23,26 the constipation is very common in elderly people, irrespective of opioid treatment,4,14,19,20 but the treatment with oxycodone-naloxone not only does not deteriorate these symptoms, however sometimes it seems to improve them:18,23-26 pain due to rib fractures could be particularly intense and the defecation could be very painful in these patients. So, pain itself could worsen the constipation,29 and the better analgesia obtained with oxycodone alone could explain the improvement in constipation. We documented nausea with a lower prevalence as previously documented,10 probably due to the lower dose prescribed. Drowsiness is quite common, but did not invalidate the adherence to treatment. We observed only one dis- continuation of these treatments, due to severe and refractory nau- sea. Our study also seems to confirm the absence of correlation between the intensity of a disease (in our case the numbers of rib fractures) and pain intensity, so pain analgesia could not be decid- ed on a pure clinical basis and it would be driven by patients’ pain scale. The short period of observation limits the evaluation of the prevalence of side effects of the association of naloxone and oxy- codone, but we could observe an improvement of constipation in some patients with preexistent condition. The rapid and the more intense analgesia, with its short-term tolerability makes the fixed association between oxycodone-naloxone a good choice in elderly patients with rib fractures. Article Table 3. Statistical analysis in pain response according to different treatment options. Oxycodone-Naloxone Oxycodone-Naloxone Oxycodone-Naloxone Oxycodone-Naloxone vs other vs Codeine-Acetaminophene vs NSAIDs or Acetaminophene vs Tapentadol or Tramadol NPS before P<0.01 P<0.01 P<0.01 P=0.831 NPS 90’ P<0.01 P<0.01 P<0.01 P=0.567 NPS 24h P<0.01 P<0.01 P<0.01 P<0.01 NSAIDs, non-steroidal anti-inflammatory drugs; NPS, Numeric Pain Scale. Non -co mmerc ial us e o nly [page 82] [Emergency Care Journal 2019; 15:8119] References 1. Shulzhenko NO, Zens TJ, Beems MV, et al. Number of rib fractures thresholds independently predict worse outcomes in older patients with blunt trauma. Surgery 2017;161:1083-9. 2. Shields JF, Emond M, Guimont C, Pigeon D. Acute minor tho- racic injuries: evaluation of practice and follow-up in the emer- gency department. Can Fam Physician 2010;56:e117-24. 3. Hanlon JT, Perera S, Newman AB, et al. Potential drug-drug and drug-disease interactions in well-functioning community- dwelling older adults. J Clin Pharm Ther 2017;42:228-33. 4. Guerriero F, Roberto A, Greco MT, et al. Long-term efficacy and safety of oxycodone-naloxone prolonged release in geri- atric patients with moderate-to-severe chronic non-cancer pain: a 52-week open-label extension phase study. Drug Des Devel Ther 2016;10:1515-23. 5. Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic non-cancer pain. Cochrane Database Syst Rev 2010:CD006605. 6. Coluzzi F, Pappagallo M. National Initiative on Pain Control. Opioid therapy for chronic non-cancer pain: practice guide- lines for initiation and maintenance of therapy. Minerva Anestesiol 2005;71:425-33. 7. McIntosh SE, Leffler S. Pain management after discharge from the ED. Am J Emerg Med 2004;22:98-100. 8. Di Pietro S, Mascia B, Perlini S, Iotti G. Levobupivacaine combined with dexamethasone for serratus plane block can provide long-lasting analgesia in multiple rib fractures. Emerg Care J 2019;15:7716. 9. Blanco R, Parras T, McDonnell JG, Prats-Galino A. Serratus plane block: a novel ultrasound-guided thoracic wall nerve block. Anaesthesia 2013;68:1107-13. 10. Vondrackova D, Leyendecker P, Meissner W, et al. Analgesic efficacy and safety of oxycodone in combination with nalox- one as prolonged release tablets in patients with moderate to severe chronic pain. J Pain 2008;9:1144-54. 11. Gatti A, Casali M, Lazzari M, et al. Prolonged-release oxy- codone/naloxone in nonmalignant pain: single-center study in patients with constipation. Adv Ther 2013;30:41-59. 12. Schutter U, Grunert S, Meyer C, et al. Innovative pain therapy with a fixed combination of prolonged-release oxycodone/naloxone: a large observational study under condi- tions of daily practice. Curr Med Res Opin 2010;26:1377-87. 13. Rosti G, Gatti A, Costantini A, et al. Opioid-related bowel dys- function: prevalence and identification of predictive factors in a large sample of Italian patients on chronic treatment. Eur Rev Med Pharmacol Sci 2010;14:1045-50. 14. Guerriero F, Sgarlata C, Marcassa C, et al. Efficacy and toler- ability of low-dose oral prolonged-release oxycodone/nalox- one for chronic nononcological pain in older patients. Clin Interv Aging 2015;10:1-11. 15. Marco CA, Plewa MC, Buderer N, et al. Comparison of oxy- codone and hydrocodone for the treatment of acute pain asso- ciated with fractures: a double-blind, randomized, controlled trial. Acad Emerg Med 2005;12:282-8. 16. Pöyhiä R, Vainio A, Kalso E. A review of oxycodone’s clinical pharmacokinetics and pharmacodynamics. J Pain Sympt Manage 1993;8:63-7. 17. Müller-Lissner S, Bassotti G, Coffin B, et al. Opioid-induced constipation and bowel dysfunction: a clinical guideline. Pain Med 2017;18:1837-63. 18. Burness CB, Keating GM. Oxycodone/naloxone prolonged- release: a review of its use in the management of chronic pain while counteracting opioid-induced constipation. Drugs 2014;74:353-75. 19. Abdulla A, Adams N, Bone M, et al. Guidance on the manage- ment of pain in older people. Age Ageing 2013;42:i1-57. 20. Trescot AM, Helm S, Hansen H, et al. Opioids in the manage- ment of chronic non-cancer pain: an update of American Society of the Interventional Pain Physicians’ (ASIPP) Guidelines. Pain Physician 2008;11:S5-S62. 21. Quattromani E, Normansell D, Storkan M, et al. Oligoanalgesia in blunt geriatric trauma. J Emerg Med 2015;48:653-9. 22. Ko A, Harada MY, Smith EJ, et al. Pain assessment and control in the injured elderly. Am Surg 2016;82:867-71. 23. Smith K, Hopp M, Mundin G, et al. Low absolute bioavailabil- ity of oral naloxone in healthy subjects. Int J Clin Pharmacol Ther 2012;50:360-7. 24. Meissner W, Leyendecker P, Mueller-Lissner S, et al. A ran- domised controlled trial with prolonged-release oral oxy- codone and naloxone to prevent and reverse opioid-induced constipation. Eur J Pain 2009;13:56-64. 25. Meissner W, Schmidt U, Hartmann M, et al. Oral naloxone reverses opioid-associated constipation. Pain 2000;84:105-9. 26. Ahmedzai SH, Leppert W, Janecki M, et al. Long-term safety and efficacy of oxycodone/naloxone prolonged-release tablets in patients with moderate-to-severe chronic cancer pain. Support Care Cancer 2015;23:823-30. 27. Singh G. Recent considerations in nonsteroidal anti-inflamma- tory drug gastropathy. Am J Med 1998;105:31S-8S. 28. Machado GC, Maher CG, Ferreira PH, et al. Efficacy and safe- ty of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo controlled tri- als. BMJ 2015;350:h1225. 29. Kokki M, Kuronen M, Naaranlahti T, et al. Opioid-induced bowel dysfunction in patients undergoing spine surgery: com- parison of oxycodone and oxycodone-naloxone treatment. Adv Ther 2017;34:236-51. Article Non -co mmerc ial us e o nly