Pediatric sleep disordered breathing is often caused by hypertrophy of the tonsils and is commonly managed by tonsillectomy. There is controversy regarding which postsurgical analgesic agents are safe and efficacious.
This prospective randomized clinical trial recruited children who had sleep disordered breathing who were scheduled for tonsillectomy +/− adenoid removal. Parents were provided with a pulse oximeter to measure oxygen saturation and apnea events the night before and the night after surgery. Children were randomized to receive acetaminophen with either 0.2–0.5 mg/kg oral morphine or 10 mg/kg of oral ibuprofen. The Objective Pain Scale and Faces Scale were used to assess effectiveness on postoperative day 1 and day 5. The primary endpoint was changes in respiratory parameters during sleep.
A total of 91 children aged 1 to 10 years were randomized. On the first postoperative night, with respect to oxygen desaturations, 86% of children did not show improvement in the morphine group, whereas 68% of ibuprofen patients did show improvement (14% vs 68%; P < .01). The number of desaturation events increased substantially in the morphine group, with an average increase of 11.17 ± 15.02 desaturation events per hour (P < .01). There were no differences seen in analgesic effectiveness, tonsillar bleeding, or adverse drug reactions.
Ibuprofen in combination with acetaminophen provides safe and effective analgesia in children undergoing tonsillectomy. Post-tonsillectomy morphine use should be limited, as it may be unsafe in certain children.
In response to: Morphine Dosing in Pediatric OSA: The Need to Customize
Original article: Morphine or Ibuprofen for Post-Tonsillectomy Analgesia: A Randomized Trial
We appreciate your interest in our research and we would like to take this opportunity to address some of your concerns. Firstly, our primary endpoint was declared a priori and is reported in our protocol registered with ClinicalTrials.gov registration. Please see https://clinicaltrials.gov/ct2/show/NCT01680939?term=morphine+ibuprofen+sleep&rank=1. Our primary endpoint states; "Safety will be assessed by comparing changes in respiratory parameters (oxygen saturation and the number of apnea events per night) following adenotonsillectomy."
With regards to your second concern relating to sample size, we appreciate that this may not have been clear in the article. We did complete a sample size calculation which was based on a pilot study (1). In the pilot phase of the study, we found that among 30 enrolled children, parental compliance with measuring respiratory parameters was 83%. Our sample size was set at 60 children per arm to obtain 50 evaluable patients with complete data sets per group. This sample size would allow (with a power of 90%) to show 5% oxygen saturation difference between the two groups with alpha of 0.05. Unfortunately, as our trial was stopped early by the DSMB we were unable to reach this level of recruitment. However, despite this, our results still achieved statistical significance.
You mentioned that our study population was heterogeneous, as would be the case in most Canadian practices. The mean age is reported in the original article and was not significantly different between the groups. To clarify, there were 3 patients under the age of three in the morphine arm, and 5 patients under the age of 3 in the ibuprofen arm. In an effort to exclude children with significant comorbidities, patients with any craniofacial abnormalities (including trisomy 21) or BMI > 30 were excluded from this study.
With respect to the question regarding dosing of morphine for post tonsillectomy analgesia, we have addressed this in our response to Drs Finley and Hong (2). Specifically, there exists a large variability in the dose of morphine used by Canadian Pediatric Health Centres to manage pain in children post-tonsillectomy. This is likely due to a paucity of literature regarding the use of opioids in children with OSA for post- tonsillectomy analgesia. As such, many major pediatric health centres, including our own (3) as well as the World Health Organization (4), and recent pediatric tonsillectomy guidelines from the American Academy of Otolaryngology-Head and Neck Surgery (5) do not have specific recommendations for opioid use in pediatric OSA patients. We believe that our study will help to highlight the concerns associated with opioid use in this population. As mentioned in our manuscript, the majority of children (65%) in our study received morphine doses of 0.2 mg/kg and 26% received between 0.25 and 0.35 mg/kg. The remaining 2 children received doses equivalent to 0.1 mg/kg. This is also consistent with the formularies of BC Children's Hospital (6) and Children's Hospital of Eastern Ontario (7), which recommend a starting dose of either 0.2- 0.5mg/kg or 0.2-0.3 mg/kg with no mention of lower dosages in the sleep apnea population.
We were unable to collect oximetry data for all children on the first post-operative night. Data was analysed as intent to treat and therefore we did not remove patients whose oximetry data was not collected. With the added post-operative discomfort, some children had difficulty sleeping with the oximeters and we did not feel this warranted exclusion.
As mentioned in our response to Drs. Finley and Hong's letter (2), bleeding was not the primary endpoint and therefore our study was not powered to address this. We conducted a systematic review prior to trial initiation that supported our use of NSAIDs and found that NSAIDs did not significantly affect bleeding (8). Our systematic review of the bleeding risks associated with NSAIDs, as well as similar findings from a Cochrane review of the subject will hopefully encourage the use of NSAIDs for post tonsillectomy analgesia (9).
We agree with LeMay et al that opioids may be safely used in the non- sleep apnea population and our study is only meant to address concerns in the pediatric OSA population for post tonsillectomy analgesia. The results of our study warrant caution for morphine use in some patients. We recommend admission and monitoring in children receiving significant doses of opioids post tonsillectomy for OSA. As well, additional education to parents and care-givers regarding potential respiratory side effects is advised. We also encourage future research in this area as more evidence is necessary in order to determine an optimal dosing strategy for these patients.
Lauren Kelly PhD Gideon Koren MD the Hospital for Sick Children, Toronto, Canada
Doron Sommer MD Jonathan Maclean MD McMaster Children's Hospital, Hamilton, Canada
The authors declare that they have no conflicts of interest.
References: 1. Khetani JD, Madadi P, Sommer DD, Reddy D, Sistonen J, Ross CJ, et al. Apnea and oxygen desaturations in children treated with opioids after adenotonsillectomy for obstructive sleep apnea syndrome: a prospective pilot study. Paediatric drugs. 2012 Dec 1;14(6):411-5.
2. Kelly LE, Koren G, Sommer DD, Maclean J. Post-tonsillectomy morphine or ibuprofen - differences in potential respiratory risks [letter to the editor] Pediatrics. 2015 Feb 8; 135(2): 307-31
3. MacPeds. Pediatric Formulary - Morphine (page 30) 2014 [cited 2015 March 16]. Available from: http://www.macpeds.com/documents/MacPedsFormulary.pdf.
4. World Health Organization. Model Formulary for Children 2010 [cited 2014 February 5]. Available from: http://www.who.int/selection_medicines/list/WMFc_2010.pdf.
5. Baugh RF, Archer SM, Mitchell RB, Rosenfeld RM, Amin R, Burns JJ, et al. Clinical practice guideline: tonsillectomy in children. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery. 2011 Jan;144(1 Suppl):S1- 30.
6. BC Children's and Women's Hospital Online Formulary [cited 2015 March 16]. Available from: http://www.pedmed.org/DrugApp/pedsearch.php.
7. Children's Hospital of Eastern Ontario. Pediatric doses of commonly prescribed medications Morphine 2011: page 7.
8. Riggin L, Ramakrishna J, Sommer DD, Koren G. A 2013 updated systematic review & meta-analysis of 36 randomized controlled trials; no apparent effects of non steroidal anti-inflammatory agents on the risk of bleeding after tonsillectomy. Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino- Laryngology & Cervico-Facial Surgery. 2013 Apr;38(2):115-29.
9. Lewis SR, Nicholson A, Cardwell ME, Siviter G, Smith AF. Nonsteroidal anti?inflammatory drugs and perioperative bleeding in paediatric tonsillectomy. The Cochrane Library. 2013.
Conflict of Interest:
None declared
To The Editors:
We read with great interest your recent article entitled: "Morphine or Ibuprofen for Post-Tonsillectomy Analgesia: A Randomized Trial". We heartily support research into this important area, but we have many concerns about this study's methodology, data analysis and conclusions.
The primary outcome measure, changes in respiratory parameters, was not defined at the outset. This prevented calculation of a sample size and power analysis. As well, apnea events were included in the primary outcome measure but were not measured. Desaturation events and apnea events seemed to be used interchangeably.
The study population was heterogeneous. The proportion of patients under three years of age, those with severe obstructive sleep apnea (OSA) or with Down Syndrome was not characterized. These are examples of higher risk patients that are seen for adenotonsillectomy at tertiary care hospitals(1). Each group ought to have their anesthetic and analgesic care tailored to their needs.
Also heterogeneous was the dosing range for oral morphine. Standard dosing for morphine does not apply to patients with severe OSA, as they may have central and obstructive mechanisms for apnea(2). Few practitioners would recommend 0.5 mg/kg orally for patients known to have OSA, and many would start with half the usual parenteral dose or less(3). The subject in this study who had respiratory complications received morphine dosing which we consider high for a patient with her history and likely should not have been discharged from hospital after her return visit.
Oximetry data was not collected for more than 25% of children on the first post-operative night. This resulted in a small number of patients whose data was analyzed for the primary outcome. As well, conclusions were made about the safety of ibuprofen in this patient population based on a small group of subjects without the power needed to assess changes in the rate of post-tonsillectomy bleeding.
Adenotonsillectomy for sleep disordered breathing is very common in children. Practitioners aim to provide safe, efficient and comfortable care to this often complex group of patients. Nonselective COX inhibitor use for post-tonsillectomy analgesia is not universal due to lingering concerns about bleeding(4). Acetaminophen combined with opioid therapy remains a mainstay of post-operative analgesic management in many centres. It is important that information about the correct dosing and dangers associated with opioid use in this vulnerable population be properly disseminated. The conclusions of this study are not in line with current management of these patients, nor do they provide a reassuring alternative.
1 Section on Pediatric Pulmonology SoOSASAAoP. Clinical practice guideline: diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics 2002;109:704-712
2 Brown KA, Laferriere A, Moss IR. Recurrent hypoxemia in young children with obstructive sleep apnea is associated with reduced opioid requirement for analgesia. Anesthesiology 2004;100(4):806-810
3 Raghavendran S, Bagry G, Detheux G, Zhang X, Brouillette R, Brown K. An anesthetic management protocol to decrease respiratory complications after adenotonsillectomy in children with severe sleep apnea. Anesth Analg 2010;110(4):1093-1101
4 Patino M, Sadhasivan S, Mahmoud M. Obstructive sleep apnoea in children: perioperative considerations. BJA 2013;111(S1):83-95.
Conflict of Interest:
None declared
To the Editors:
We would like to thank Dr. Kelly and her colleagues1 for their study of pain treatment for children with sleep disordered breathing who underwent tonsillectomy +/- adenoidectomy. The authors conclude that post- tonsillectomy oral morphine use should be limited, as it may be unsafe in certain children, and point out the numerous a priori reasons why this patient population is at particular risk for oxygen desaturation.
While we agree with their conclusions for sleep-disordered children undergoing surgery, we would like to caution clinicians against the broader application of this conclusion to otherwise healthy children. In fact, most children receiving appropriately dosed oral morphine do not suffer oxygen desaturation, and are not at-risk for dangerous complications. Measures of oxygen saturation may naturally fluctuate and are further influenced by factors such as coughing, retching, slip of the probe, temperature of hand, child positioning, etc. The mean length of time for oxygen desaturation periods was also not specified in the Kelly trial. Further, there are at least 7 published studies of oral morphine use in healthy children (Beale 2001; Borland 2005; Hunt 1999; Poonai 2014; Vall?e 2008; Wille 2005; Wille-Ledon 2011). Three of these studies2-4 measured oxygen saturation and none of these 7 studies reported hypoxia or any other serious adverse events.
We are currently conducting a Canadian Institutes of Health Research- funded randomized clinical trial of children presenting with a limb injury to one of three Canadian pediatric emergency departments (The OUCH Trial, clinicaltrials.gov NCT02064894). We have recruited 327/500 patients, aged 6 to 17 years, to this three-arm trial; 262 children have received oral morphine, alone, or in combination with ibuprofen. All of these children have undergone continuous emergency department observation as well as assessment of vital signs, including oxygen saturation, pain score, sedation level, and side effects every 30 minutes for a minimum of two hours after receiving oral morphine. None of these patients have experienced oxygen desaturations.
There is no doubt that ibuprofen is a good choice for the treatment of mild to moderate pain in children.5 However, some children with moderate, and most children with severe pain will require adjuvant opioid analgesia for their at-home treatment. Oral morphine should remain an option at this time, for the treatment of moderate to severe pain, as there is no evidence to date to suggest that it is not safe for otherwise healthy children with acute injuries or non-respiratory/obstructive conditions.
Sylvie LeMay, RN, PhD, University of Montreal, Montreal, Quebec, Canada Amy Drendel, DO MS, Medical College of Wisconsin, Milwaukee, Wisconsin, USA Samina Ali, MDCM, University of Alberta, Edmonton, Alberta, Canada, For the OUCH Study Team
1. Kelly LE, Sommer DD, Ramakrishna J, et al. Morphine or Ibuprofen for Post-Tonsillectomy Analgesia: A Randomized Trial. Pediatrics 2015;135:307- 313. 2. Borland M, Jacobs I, King B, O'Brien D. A Randomized Controlled Trial Comparing Intranasal Fentanyl to Intravenous Morphine for Managing Acute Pain in Children in the Emergency Department. Annals of Emergency Medicine 2007; 49(3): 335-45. 3.Wille C, Bocquet N, Cojocaru B, Leis A, Ch?ron G. Oral Morphine Administration for Children's Traumatic Pain. Archives de P?diatrie 2005;12:248-53. 4. Wille-Ledon C, Chappuy H, Giraud C, Tr?luluyer JM, Ch?ron G. Comparison of a Morphine and Midazolam Combination with Morphine Alone for Paediatric Displaced Fractures : A Randomized Study. Acta Paediatrica 2011; 100(11): e-203-7. 5. Clark E, Plint AC, Correll R et al. A Randomized, Controlled Trial of Acetaminophen, Ibuprofen, and Codeine for Acute Pain Relief in Children with Musculoskeletal Trauma. Pediatrics 2007; 119: 460-7.
Conflict of Interest:
None declared
In response to: Morphine or ibuprofen? Still no answer to the question...
Original article: Morphine or Ibuprofen for Post-Tonsillectomy Analgesia: A Randomized Trial
We wish to thank Drs. Finley and Hong for their interest in our study and for their thoughtful comments. Regarding differences in bleeding rates, the sample size of our study was not powered to discern differences in bleeding rates, as it was not our primary end point. However, prior to commencing this study we conducted a meta-analysis of all studies examining NSAIDS and bleeding after tonsillectomy. Based on a large number of studies in over 1700 children, we did not detect an increase in bleeding rates following NSAID use (1).
For clarification the Objective Pain Scale and Modified Faces Scale were assessed at several time points (every 6 hours) over the course of Day 1 and Day 5 and do not reflect single point analysis. While we agree that measuring pain every few hours, on each post-operative day may have provided a more complete picture of recovery, we felt that this daunting request may act as a barrier to caregiver protocol compliance.
A recent report by the Council of Canadian Academies highlights this issue of off-label medication use in Canadian children (2) and morphine is one of the most common culprits (3, 4). The fact that morphine remains off -label for this indication has led to variability in the dose of morphine used by Canadian Pediatric Health Centres to manage pain in children post- tonsillectomy. We believe that there is a paucity of literature regarding the use of opioids in children for post-tonsillectomy analgesia. As such, the morphine dose selected in our study is consistent with the guideline dose schedules used by the Hospital for Sick Children, McMaster University Medical Centre and other institutions. Furthermore the WHO Model Formulary for Children (2010) also lists 0.2-0.5 mg/kg/q4h as the recommended morphine dose for children ages 2-12 (5). Moreover, a report published recently from Western University used 0.5mg/kg (6), and a study from Sherbrooke employed a post-tonsillectomy morphine dose of 0.3mg/kg (7). In our experience at McMaster, we do occasionally see children who require additional analgesia following pain management with ibuprofen and acetaminophen. In such rare cases, we prescribe a low dose morphine script (0.05-0.1 mg/kg) and depending on severity admit overnight.
It does make pharmacological sense that the respiratory depression induced by morphine is dose dependent. However, there is an important point that escapes the radar all too often: following tonsillectomy for obstructive sleep apnea, an estimated 25-34% of children continue to exhibit apnea for days and even months (8) . The idea of sending such children home on a respiratory depressant such as an opioid warrants caution. The fact that ibuprofen appears to be effective and safe is therefore a key message of our study. We agree with Drs. Finley and Hong that low dose morphine (perhaps as low as 0.05-0.1 mg/kg) may be required as breakthrough doses for some children in whom acetaminophen and an NSAID provide insufficient analgesia. However, our findings suggest that this is the exception, rather than the rule. Furthermore, we urge increased vigilance and parental education in these cases.
Lauren Kelly PhD, Gideon Koren MD the Hospital for Sick Children, Toronto, Canada
Doron Sommer MD, Jonathan Maclean MD McMaster Children's Hospital, Hamilton, Canada
The authors declare that they have no conflicts of interest.
References:
1. Riggin L, Ramakrishna J, Sommer DD, Koren G. A 2013 updated systematic review & meta-analysis of 36 randomized controlled trials; no apparent effects of non steroidal anti-inflammatory agents on the risk of bleeding after tonsillectomy. Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino- Laryngology & Cervico-Facial Surgery. 2013 Apr;38(2):115-29. PubMed PMID: 23448586.
2. t Jong GW, Klassen TP, MacLeod SM. A Landmark Report on Improving Medicines for Children. JAMA pediatrics. 2015 Jan 5. PubMed PMID: 25561323.
3. Hsu B, Brazelton T. Off-label medication use in an academic hospital pediatric critical care unit. WMJ : official publication of the State Medical Society of Wisconsin. 2009 Oct;108(7):343-8. PubMed PMID: 19886581.
4. Conroy S, Choonara I, Impicciatore P, Mohn A, Arnell H, Rane A, et al. Survey of unlicensed and off label drug use in paediatric wards in European countries. European Network for Drug Investigation in Children. Bmj. 2000 Jan 8;320(7227):79-82. PubMed PMID: 10625257. Pubmed Central PMCID: 27251.
5. Organization WH. Model Formulary for Children 2010 [cited 2014 February 5]. Available from: http://www.who.int/selection_medicines/list/WMFc_2010.pdf.
6. Poonai N, Bhullar G, Lin K, Papini A, Mainprize D, Howard J, et al. Oral administration of morphine versus ibuprofen to manage postfracture pain in children: a randomized trial. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. 2014 Dec 9;186(18):1358-63. PubMed PMID: 25349008. Pubmed Central PMCID: 4259768.
7. Vallee E, Lafrenaye S, Tetrault JP, Mayer S, Dorion D. Pain management after tonsillectomy: morphine is not enough. Journal of otolaryngology - head & neck surgery = Le Journal d'oto-rhino- laryngologie et de chirurgie cervico-faciale. 2008 Apr;37(2):279-84. PubMed PMID: 19128627.
8. Friedman M, Wilson M, Lin H-C, Chang H-W. Updated systematic review of tonsillectomy and adenoidectomy for treatment of pediatric obstructive sleep apnea/hypopnea syndrome. Otolaryngology-Head and Neck Surgery. 2009;140(6):800-8.
Conflict of Interest:
None declared
To the Editors:
We read with great interest the recent article by Kelly et al., entitled "Morphine or Ibuprofen for Post-Tonsillectomy Analgesia: A Randomized Trial" published in Pediatrics. 1 This study describes the importance of appropriate pain management post-tonsillectomy, and has generated considerable media attention in Canada. While this article is interesting, there are some issues that require clarification.
First, the sample size is too small to make some of the conclusions stated. Although we would welcome a shift in standard practice toward the use of ibuprofen or other non-steroidal anti-inflammatory drugs (NSAIDs), as suggested by the authors, the current study did not have enough subjects to show a meaningful difference from morphine in postoperative bleeding rates, which are also, of course, dependent on surgical technique, local infection, and other factors. We do realize that the study ended prematurely, but it is most unfortunate that the opportunity to make a valid statement about safety of NSAIDs was missed.
Second, the Objective Pain Scale is not a currently accepted standard for pain measurement in clinical trials, and will tend, like most behavioral and physiological scales, to attenuate over a short period of time, resulting in failure to show differences in pain outcomes. 2-4 The authors also stated that they used a "modified Faces scale", and cited a paper by Hamers (2002). 5 However, Hamers used a visual analogue scale (VAS), not a Faces scale, so we cannot evaluate the scale used in this study. In any case, measuring pain intensity only at two points (days 1 & 5) may miss important variations in pain over the post-operative period.
Most importantly, the stated dosages of morphine given during at-home use (0.2-0.35 mg/kg) would be considered very high for tonsillectomy patients by most clinicians. Patients from our centre are sent home with instructions to use morphine 0.1 mg/kg every 4 hours as needed, in addition to a regular regimen of acetaminophen. We find that post- tonsillectomy pain is usually very well controlled with this dose of morphine. It should not be surprising that desaturation rates were increased with the doses used in the current study. The patient described who suffered respiratory depression at home had been receiving excessive doses of morphine - her complication was clearly due to dose, not drug.
Although it was entirely appropriate to discontinue use of codeine in pediatric patients, due primarily to its frequent inefficacy, as well as the occasional rapid metabolism and over-effect, we should be careful not to throw the baby out with the bathwater on the basis of one rather small study. A transition to regular doses of NSAIDs instead of opioids for routine post-operative pain management after tonsillectomy would be entirely appropriate, if a well-designed study can properly assess pain relief and the risks of both bleeding and respiratory complications.
Sincerely,
G. Allen Finley, MD FRCPC FAAP and Paul Hong, MD FRCSC IWK Health Centre Halifax, Canada
REFERENCES 1. Kelly LE, Sommer DD, Ramakrishna J, et al. Morphine or Ibuprofen for Post-Tonsillectomy Analgesia: A Randomized Trial. Pediatrics 2015;135:307- 313. 2. Beyer JE, McGrath PJ, Berde CB. Discordance between self-report and behavioral pain measures in children aged 3-7 years after surgery. J Pain Symptom Manage 1990;5:350-356. 3. McGrath PJ, Walco GA, Turk DC, et al. Core outcome domains and measures for pediatric acute and chronic/recurrent pain clinical trials: PedIMMPACT recommendations. J Pain 2008;9:771-783. 4. von Baeyer CL, Spagrud LJ. Systematic review of observational (behavioral) measures of pain for children and adolescents aged 3 to 18 years. Pain 2007;127:140-150. 5. Hamers JP, Abu-Saad HH. Children's pain at home following (adeno) tonsillectomy. Eur J Pain 2002;6:213-219.
Conflict of Interest:
None declared