Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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When the analgesia wears off...
- Gail Eva (3 February 2001)
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Intramuscular analgesia is out of vogue
- M A Chaudhry (4 February 2001)
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Nasal rote may not be the best
- N G Mandal (6 February 2001)
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Randomised to Sniffing Heroin
- Claudius Rudin (6 February 2001)
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Don't forget to splint injured limbs.
- Roderick Duncan (6 February 2001)
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Duration of analgesia
- Vince Summers (6 February 2001)
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Is intramuscular morphine a good outcome for comparison?
- Vicente Ruiz-Garcia (7 February 2001)
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More questions than answers
- Norbert Klöcker (9 February 2001)
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IM injections hurt - but is intranasal diamorphine better than current practice?
- Gregory Larkin (14 February 2001)
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Diamorphine in children Really ?
- Axel Schnuch (19 February 2001)
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Re: Diamorphine in children.
- Theo Fenton (20 February 2001)
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Use of nasal diamorphine for analgesia in children and teenagers
- Eric A Voth, Richard Schwartz (25 April 2001)
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Nasal Diamorphine as an analgesic agent - response from authors
- Jason Kendall (10 May 2001)
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The pharmacokinetics of intranasal diamorphine
- James Robert Craig (1 June 2001)
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Gail Eva, Clinical Lead Occupational Therapist Oxford Radcliffe Hospitals Trust
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I was interested to read the study showing the advantages of nasal diamorphine, having had personal experience of its benefits. When my five year old son, Nicholas, was recently admitted to A&E with a fractured collarbone, nasal diamorphine was administered with all of the good effects described by the authors. However, I would like to raise a point for consideration: the effects wear off quite quickly. In our case, diamorphine was administered at 6am, Nicholas was supplied with a piece of triangular cotton and discharged home. By 10am, he was in severe pain, and for the following 12 hours or so, he was extremely distressed. The combination of ibuprofen & paracetamol prescribed by the hospital was NOT adequate. When I rang the GP to request something more effective, I was told she could not help: if we had a problem, we should take him back to hospital. Even had I been able to face another 6 hour wait in A&E, this was impossible - he screamed when he moved. We persevered at home, and worked on distraction. (There is scope somewhere for a study to investigate the analgesic effects of old Disney films.) Nasal diamorphine is evidently effective, safe and easy to administer. May I appeal to the doctors using it for children in A&E to make adequate provision for the child to manage once its effects have worn off. |
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M A Chaudhry, SpR A&E University Hospital Selly Oak Birmingham
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Kendell et al[1] article comparing nasal diamorphine with intramuscular morphine in children and teenagers with acute pain certainly provides an interesting idea for emergency physicians to consider.Unfortunately, they chose to compare nasal diamorphine with intramuscular injection of morphine- a practice that has been abandoned by many deparments. To my knowledge, most of depatments nowadays use either oramorph for small children or IV morphine for teenagers. You do not need to inflict torture of intramuscular injection to prove significant P value. Of course, children, parents and staff will be biased and react adversly to intramuscular analgesia.Moreover, absorption , efficasy and safety is unpredictable following intramuscular injection. Probabally, it would have been more practicle, had they compared nasal diamorphine with oramorph in small children. In this way they could have avoided non-blinding with cross over design that certainly have affected their results.For relief of acute pain in small children,use of oramorph appears to be prevailant practice in my expereince and it is backed up by the evidence[2]. 1 KendallLM, Reeves BC, Victoria S. Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures.BMJ 2001;322: 261-5. 2 Jacobson SJ, Kopecky EA, Joslin P. Randomised trial of oral morphine for painful episodes of sickle cell disease in children Lancet 1997; 350: 1358-61. |
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N G Mandal, Specialist Registrar in Anaesthetics Poole, UK
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Editor - I was interested to read the article by Kendall and colleagues [1]. I would like to make a few comments on their study. The authors [1] found that the onset of pain relief was faster in the spray group than in the intramuscular group. Diamorphine is more lipid soluble than morphine and thus it crosses the blood brain barrier faster. This may be the reason for producing faster onset of action. However, the faster onset of pain relief in diamorphine group may not be clinically significant. The nasal spray was not as effective as claimed by the authors [1]. They noted that 36 patients in nasal group were still suffering from moderate to severe pain (Wong Baker face pain scores 4 or more) after 20 and 30 minutes of first analgesic dose. This clearly indicates that a single nasal spray of diamorphine was inadequate to provide fast and effective pain relief for a large number of patients. It is well known from our daily experiences that the intramuscular route is unpleasant, traumatic, slow and unpredictable. In the situations of acute pain an intravenous cannula could provide the best possible route for delivering analgesic drugs. Tritrating doses of an intravenous opioid can control acute pain effectively in a very short period of time. Even intravenous ketorolac was found to be as effective as intravenous morphine with very little side effects [2]. Assessment of the adequacy of analgesia by the need for rescue analgesia may not be correct [1]. Although many patients in either group were suffering from moderate to severe pain after 20 and 30 minutes of first analgesic dose, only a small number of them opted for a rescue analgesic. Proportionately more patients with moderate to severe pain in nasal group received rescue analgesic compared to intramuscular group (25% & 30.5% versus 15% & 23.8% at 20 & 30 minutes respectively). This indicates that many of them were afraid of a painful intramuscular injection. The amount of analgesic used from an on-demand intravenous rescue analgesic device could provide a better indicator of adequacy of analgesia. It could be argued that inserting an intravenous cannula is painful and unnecessary. However it could be more acceptable to have a single intravenous cannula rather than having repeated intramuscular injections. If time permits then a tropical local anaesthetics could be helpful for a painless venous cannulation. Moreover, in many patients with trauma an intravenous cannula would be necessary for future use to administer other medications. This approach could achieve better results and patient’s satisfaction. The authors claimed that “nasal diamorphine spray may be the best way to provide analgesia for young people in different circumstances”. This may not be the case. There are many other ways to provide better analgesia than nasal diamorphine spray. However, nasal route should be preferred to intramuscular route. A study comparing intravenous and nasal routes could have been more useful. Dr Nanda Gopal Mandal, Specialist Registrar in Anaesthetics
References: 1. Kendall JM, Reeves BC, Latter VS on behalf of the Nasal Diamorphine Trial Group. Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures. BMJ 2001; 322:261-5(3 February 2001) 2. Rainer TH, Jacobs P, Ng YC, Cheung NK, Tam M, Lam PKW, Wong R, Cocks RA. Cost effectiveness analysis of intravenous ketorolac and morphine for treating pain after limb injury: double blind randomised controlled trial. BMJ 2000; 321: 1247-51 |
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Claudius Rudin, Senior Clinical Fellow Leukaemia and Myeloma Units, Royal Marsden Hospital, Downs Road, Sutton, Surrey, SM2 5PT
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I congratulate Kendall et al (1) to successfully testing an additional form of highly active analgesia for the out-patient setting, particularly as it serves to further underline the important pharmacological advantages that justify the medical use of diamorphine. However, as I consider the potential for introducing nasal diamorphine as an adjunct to local anaesthetic for bone marrow trephine biopsies in my own practice, I am left wondering about issues of consent. In short, how did the Nasal Diamorphine Trial Group explain to the parents that the trial involved random allocation of their children to either intramuscular morphine or sniffing heroin? I would also be interested to know what some of the initial concerns raised by the research ethics committees in this respect were and how the trial group responded to them. Yours sincereley, Claudius E Rudin (1) Kendall JM, Reeves BC, Latter VS. Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures. BMJ 2001;322:261-5. |
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Roderick Duncan, Consultant Paediatric Orthopaedic Surgeon Royal Hospital for Sick Children
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The paper by Kendall et al (1)is a valuable addition to the literature on the management of children's fractures. It is interesting to note, however that the authors have not mention immobilisation of the limb as a factor in producing pain relief. It is not clear from the paper whether the injured limbs had been immobilised before or after administration of either the intramuscular morphine or the intranasal diamorphine. One of the things that is disappointing when teaching medical students and junior doctors is that, when asked the simplest way to provide analgesia for an individual with a fracture, they reply with reference to the "analgesic ladder". Fortunately our ambulance colleagues and first aiders are aware that splintage of an injured limb is a very effective method of providing pain relief. Unfortunately it is only too common an occurrence to come across radiographs of clinically deformed limbs without evidence of a splint having been applied. Please don't forget it - it can be simple and is very effective, and I would wish it for my children in addition to intranasal diamorphine. 1.Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures Jason M Kendall, Barnaby C Reeves, and Victoria S Latter BMJ 2001; 322: 261-265 |
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Vince Summers, Trust Chief Pharmacist Borders General Hospital
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Gail Eva's response to the article has quite rightly pointed out that the duration of analgesia from a single dose of nasal diamorphine is very unlikely to last beyond 4 hours. It is worth noting that none of the most commonly used opioids given in this type of clinical situation (diamorphine, morphine, pethidine etc.)are likely to give any greater duration of analgesia. This reinforces the need for an analgesic strategy after the initial dose. |
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Vicente Ruiz-Garcia, MD PhD Unidad de Hospitalización a Domicilio. Hospital La Fe. Avda de Campanar s/n Valencia SPAIN
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Dear Editor: It was with much interest that we read Kendall’s paper titled “ Multicentre randomised controlled trial ...” We would like to point out that the oral administration of morphine is still the most widely used in pain management that with other drugs is not possible. The alternative to this method of administration is subcutaneous or rectal (1). Intramuscular administration is not recommended because of poor and erratic bioavailability in blood (2). We are therefore surprised by the choice of this method of administration as an outcome for comparing the new treatment. Clinical trials of new drugs must compare the new presentation with the best possible option (3).If not then the sense is given that the new drug has been specifically selected for what it is intended to prove. That intranasal administered diamorphine is as effective as intramuscular administered diamorphine offers nothing new to existent knowledge, as even in burns patients oral and/or rectal administration remain in the first line of treatment. (1) Jacox A, Carr DB, Payne R New Clinical-Practice Guidelines for the Management of Pain in Patients with Cancer N Engl J Med 1994 Mar 3;330(9:651-5 (2) Practice guidelines for cancer pain management. A report by the American Society of Anesthesiologists Task Force on Pain Management, Cancer Pain Section. Anesthesiology. 1996 May;84(5:1243-57 (3) Bero LA, Rennie D Influences on the quality of published drug studies Int J Technol Assess Health Care 1996 12(2:209-237 1Vicente Ruiz-García MD PhD 2Rosana Peiró RN MPH 1 Unidad de Hospitalización a Domicilio. Hospital La Fe. Generalitat Valenciana. 2Centro de Salud Pública Alzira. Dirección General de Salud Pública. Generalitat Valenciana. Correspondence:
Vicente Ruíz-García. MD PhD,
Unidad de Hospitalización a Domicilio. Hospital La Fe. Generalitat
Valenciana.
Avda de Campanar s/n
Valencia
SPAIN
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Norbert Klöcker, Medical Director AUDIT Institute for Medical Services and Quality Assurance
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Editor-With interest I read the results of Kendall et al on a pilot clinical trial in children and teenagers of nasal diamorphine compared to intramuscular morphine 1. This study with a re-markable number of patients participating adds further evidence to the well known efficacy of nasally applied opioids. It has been shown that the nasal route of application can be a valuable alternative to existing treatments and that various opioids are effective, in general the smaller and more lipophillic the molecule the better the efficacy. This applies also for various other substances, where nasal application provides advantages 2. However, only one nasal pain-killer is commercially available (USA, Stadol®NS, active ingredient: Butorphanol). One of the major problems in pain therapy is the enormous variability of subjective pain as-sessment and interindividual response on therapeutical doses. In simple words: the pain easily tolerable for me can be absolutely intolerable for you, while the dose of analgesic not affecting my pain at all can cause serious side effects, in particular breathing depression, in you. This makes a fixed dose regimen difficult and has led to the concept of patient controlled analgesia (PCA), a therapeutical approach also under investigation in nasal pain therapy 3,4,5. The study performed by the Nasal Diamorphine Trial Group leaves a series of questions unanswered. First of all, the open design allows no real comparison. The authors claim, the use of the "double dummy" technique was considered unethically. Who decided so, and why was it ethically justified to give injections to one half of the study population while it was considered unethical to treat the other half identically? It is obvious that the results are biased by the comparison of an invasive to a non-invasive treatment. Assessment by a face pain scale might be a valid method for efficacy measurement, as objective outcome measures do not exist for this kind of study. However, the authors state that they did collect data from visual analogue scales also and it would be valuable to see, whether they give the same answers as the face pain scale. Even if the visual analogue scales were only performed in a subgroup, namely in the older children, they might reflect more the "truth" than the facial expression of a traumatised small child in a strange environment (as hospitals usually are) with scaring strange people all around. Why was morphine chosen as the comparator and not diamorphine, or fentanyl, or other es-tablished (and registered) therapeuticals in severe pain? Why was the intramuscular application chosen and not the intravenous? Do we compare apples with pears? Why was a dry powder with diluent chosen and not a ready-to-use nasal spray with proven pharmaceutical stabilityfor an acceptable time (the authors state accordance to ICH-guidelines, but this subject is certainly not in accordance!). The procedure used would be acceptable for a feasibility study (which allready have been performed and published), but why was this unsatisfactory approach used in over 400 children? The authors state that there was a motivation factor influencing the recruitment rate and about half of the study-centres can be judged as poor performers. Have the authors performed a statistic test if there was an inter-rater variability? It would be valuable to learn, how long the treatments were effective. The simplest way to assess this is the time intervall to rescue medication. Again, the injection group might be biased as the first injection was already painfull and scaring, thus that experience might have kept the children, especially in small ones, from asking for a second injection. How were the nasal sprays prepared. We do not know which volume was used, only that a dose of 0.1 mg/kg was used. The information given in the paper could lead to the conclusion that for each mg of diamorphin 0.1 ml was applied, which certainly wold cause epipharyngeal congestion. How was the diamorphin-preparation transferred into the spray systems, and by whom? Small volumes need extreme accuracy and loss in the system has to be taken into acount, usually such work is performed by skilled staff, eg pharmacists, but the authors leave this information open. How is the accuracy of the device used? Why was the, yet unknown, device chosen as the acceptible onefor this ethically serious study? Usually nasal spray devices work only in an upright position, therefore often difficult to use in a clinical setting, especially with traumatised patients. Did the patients thus have to sit up for drug application (which could cause addidional pain)? It would, furthermore, be interesting to know the physico-chemically parameters of the diamorphin-preparation, namely pH, viscosity and osmolality, all parameters affecting nasal absorption. Which nostril was used for nasal application? The better ventilated (how did they know?), a randomised one, always the right or left, or by chance? The authors state that over the half of the adverse events involved irritation at the site where the drug was given. Does that mean that the spray had a very low pH (as usual for many in-jectables)? It would be valuable to learn about local tolerability of the diamorphin nasal spray. Has anybody inspected the mucosal status for signs of irritation or swelling? Finally, after reading the paper a second time, there were more questions than answers to me. 1.Kendall LM, Reeves BC, Vuctoria S. Multicentre randomised controlled trial of nasal diamorphine for alalgesia in children and teenagers with clinical fractures. BMJ 2001;322: 261-5 2.Klöcker N, Hanschke W, Toussaint S, Verse T. Scopolamine nasal spray in motion sickness: a randomised, controlled, and crossover study for the comparison of two scopolamine nasal sprays with oral dimenhydrinate and placebo. EJPS 2001 (in print) 3.Striebel HW, Toussaint S, Raab C, Klöcker N. Non-invasive methods for PCA in pain management. Acute Pain 1999; 2: 36-40 4.Toussaint S, Maidl J, Schwagmeier R, Striebel HW. Patient-controlled intranasal analgesia: effective alternative to intravenous PCAfor postoperative pain relief. Can J Anaesth 2000; 47: 299-302 5.Hallett A, O'Higgins F, Francis V, Cook TM. Patient-controlled intranasal diamorhin for postoperative pain: an acceptability study. Anaesthesia 2000; 55: 532-9 Norbert Klöcker MD, PhD, MFPM
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Gregory Larkin, Visiting Professor in Emergency Medicine Emergency Department, St Thomas' Hospital, London
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Editor: We read with interest the study by Kendall et al [1] of an RCT examining the use of nasal diamorphine in children and teenagers with clinical fractures. We are unclear how the authors determined that intramuscular morphine is “the standard treatment” or the conclusion that “Nasal diamorphine may be the best way to provide analgesia for young people in different circumstances.” The British Association of Accident & Emergency Medicine (BAEM) has established national Guidelines for Analgesia in Children in the Accident & Emergency Department that do not include intramuscular (IM) analgesia of any kind [2]. Even the Americans have long abandoned the practice of using IM medications for analgesia in children, [3] Hence, the trial answers questions that few clinicians are actually asking, as the comparison group is no longer relevant to modern emergency medicine practice. More information could have been gleaned by using oral or intravenous morphine, currently the recommended routes of morphine administration by the BAEM for analgesia in children with moderate and severe pain, respectively. Given that nearly half of the patients given diamorphine remained in pain after twenty minutes, it is unlikely that nasal spray will replace IV opiates yet. There are other methodological concerns with this work as well: the use of a convenience nonrandom sample, unblinded raters, lack of interobserver agreement data, unclear enrollment time frames, unanswered economic questions, using parametric statistics for non-normal and ordinal data, equating the Wong Baker to another undefined VAS, treating toddlers and teens as equals (eg. GCS is unvalidated in toddlers), and lack of follow-up data regarding both diagnosis and outcome. These generate more questions than answers about the utilization of nasal diamorphine in children. The data presented is incomplete. For example, GCS, respiratory rate, and oxygen saturation data are not provided, we suggest editing out conjecture and such unconventional devices as personal communication with oneself while retaining important details in the methods and results sections. Applying Occam’s razor results in egregious obfuscation of untoward events as demonstrated in the following statement: “Overall, 84 non-serious adverse events occurred; all were mild except for one in the spray group that was considered severe.” The juxtaposition of terms “non- serious,” “all were mild except ..one….was severe.”…is the height of rationalization and has no place in objective academic inquiry. We can deduce that 12 more patients in the spray group had adverse events, and almost one quarter of patients overall, but greater detail is needed to allow clinicians to judge for themselves whether these events were serious or not. Were these events more common in toddlers or teens? Similarly, we are told that “median oxygen saturation was slightly lower in the spray group,” but neither the magnitude of the difference nor a definition of slightly are provided. Fully 8% in the spray group had a oxygen desaturation event, but again we are not told who these patients were and to what level the oxygen fell and for how long or whether or not oxygen, naloxone, assisted ventilation, or other measures had to be applied. These are the kinds of safety data that make an article relevant to clinicians. In summary, this study shows that IM injections hurt and that nasal diamorphine can reduce pain. The most interesting questions that would change clinical practice, however, remain unanswered. Gregory Luke Larkin MD MS MSPH FACEP
Peter Leman MB BS MRCP FRCSEd FFAEM DFPHM MSc
[1] Kendall JM, Reeves BC, Latter VS. Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures. BMJ. 2001; 322: 261-265 [2] www.baem.org.uk/pedangls.htm. accessed 9th February 2001 [3] Pomeranz ES, Kulick RM in Tintinalli JE, Ruiz E, Krome RL eds Emergency Medicine, a Study Guide, McGraw-Hill, New York, 1996. p 256. |
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Axel Schnuch, md IVDK/ Univ.-Hautklinik / Goettingen / Germany
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Madam, Sir, Highly surprised I read that diamorphine was used in a clinical study in children, and that it is "currently being evaluated in adults for the control of breakthrough pain in patients revceiving palliative care and in surgical patients for postoperative analgesia" (1). The reason for my confusion is the fact that diamorphine (BAN) or Diacetyl Morphine (USP) is identical to Heroin (originally the Bayer brandname). If the drug in question was not Heroin, then the drug used in that trial should be named correctly, allowing for identification. However, if it was Heroin, obviously, some questions remain: 1. Who purchased the drug (the phrase "we were provided with..." is
not very informative)
Anyway, your readers should be informed that, following the nomenclature of international pharmacopeias , Diamorphine (Diacetyl Morphine) is nothing but Heroin. This was not mentioned in the article. With kind regards Axel Schnuch, MD
Kendall JM et al Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures BMJ 322, 261-5 (2001) |
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Theo Fenton, Consultant Paediatrician Mayday Hospital, Croydon
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Sir, Dr Schnuch states that Heroin is the Bayer brand name for diamorphine. Kendall et al were therefore right not to refer to their diamorphine as Heroin, as they obtained it from a different manufacturer (CP Pharmaceuticals). The British National Formulary states that brand names may in general be applied only to products supplied by the owners of the trade mark. CP Pharmaceuticals is one of a number of 'generic' manufacturers who may produce pharmaceuticals after the inventor's patent has expired. Doctors in Britain (unlike doctors in the USA) can (and do) prescribe diamorphine for acute and chronic pain, in both adults and children. Dr Schnuch takes the emotive view that the authors must tell the parents that the drug is identical to heroin. Would he be similarly surprised if an even more potent opiate such as fentanyl were given in children? Well, it often is. The Royal College of Paediatrics and Child Health encourages us to move away from the idea that it is unethical to do drug trials in children. Indeed, The College believes that it is unacceptable not to do the trials as effective childhood treatments might otherwise not be identified. Yours faithfully, Dr Theo HM Fenton
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Eric A Voth Institute on Global Drug Policy, St Petersburg, Florida, Richard Schwartz
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It is imperative that readers understand that Kendall et al. (1) are advocating the snorting of heroin (diamorphine) for children and adolescents for pain control. The authors have already identified the use of fentanyl and meperidine via nasal administration so one must ask, "Why heroin?" The use of heroin has an earlier onset of analgesia as measured by the WongBaker face pain scale. However, the authors fail to realize or account for the fact that morphine measurements must overcome the secondary pain of sticking a needle deeply into the muscle of the unsuspecting child. This usually elicits a less-than-appreciative response from the child, and it confounds the measurement of the onset of pain relief. A goodly amount of time is usually necessary to comfort the child from the injection alone. Indeed, the analgesia was equal at 30 minutes. The study would have been further strengthened had intranasal morphine been attempted as a comparison or even as a third study group. Certainly, comparison studies with fentanyl, morphine, and benzodiazepine/opioid mixtures should be done before adopting the use of heroin. The big picture is that there is no need to open the door to the medicinal use of heroin, and there is certainly no need to open it for the use in children unless it can be shown to be unequivocally better than existing products. This article certainly does not succeed in that arena. Sincerely, Eric A. Voth, M.D., FACP
Richard Schwartz, M.D. FAAP Institute on Global Drug Policy, Box 11298, St Petersburg, Florida 33733-1298 1. Kendall JM, Reeves BC, Latter VS. Multicentre randomised controlled trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures. BMJ 2001;322:261-265 |
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Jason Kendall, Consultant in Emergency Medicine North Bristol NHS Trust
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A number of issues about our paper, "Multicentre randomised
controlled trial of nasal diamorphine for analgesia in children and
teenagers with clinical fractures" (1), have been raised by
correspondents:
Each of these issues is addressed separately below, although there is sometimes overlap between individual items. (a) The need for adequate analgesia at the time of discharge The point made by Gail Eva and Vince Summers, about the need for adequate analgesia once the effects of nasal diamorphine have worn off, is well made but is usually only a concern for a minority of children. The majority of children in the study, which reflects of everyday practice, presented with a fractured radius and ulna. The most effective longer term analgesic strategy for most of these children is immobilisation of the fracture by splinting (see (b) below), although a significant proportion will require manipulation of the fracture under general anaesthetic. When manipulation is necessary, analgesia can be given intravenously (via a cannula placed through anaesthetised skin following the application of a suitable topical anaesthetic agent), after achieving immediate analgesia with nasal diamorphine (see (d) below). Any further analgesia that may be required (in addition to anaesthetic agents) can be delivered by the intravenous route. Immobilisation is not practical for a minority of patients who, for example, sustain injuries such as a fractured clavicle (like Gail Eva's son). In this situation, it is standard practice to support the injured limb in a sling and to use a combination of simple analgesia (e.g. paracetamol) and a non-steroidal anti-inflammatory medication (e.g. ibuprofen or diclofenac). This combination usually provides adequate control of symptoms. Unfortunately, as stated by Vince Summers, none of the opioids have a duration of effect that would provide adequate analgesia after discharge from the emergency department and these agents are not suitable for out-patient use in this setting. (b) The need to splint fractures Roderick Duncan discusses the vital role played by splinting fractures as an analgesic intervention. Indeed, splinting a fracture is probably the single most effective intervention after initial analgesia has been administered (the actual procedure of applying the splint is painful because it requires movement of the affected limb). In the trial, wherever appropriate, fractures were splinted at the earliest opportunity. Typically, children receive analgesia upon presentation, have an x-ray organised and are splinted. This is standard practice within emergency departments. (c) The appropriateness of using intra-muscular morphine as the comparator Morphine can be administered as emergency analgesia by injection or orally. The former is poorly tolerated and the latter is inadequate because of delayed gastric emptying, unpredictable bioavailability and first-pass metabolism. Although unsatisfactory, intra-muscular analgesia was still standard practice in a number of emergency departments at the time that the study was approved in 1996-7. At this time the Local Research Ethics Committees and the staff in each participating hospital considered that intra-muscular morphine sulphate was a suitable comparator. The faster onset of analgesia with nasal diamorphine compared with intramuscular morphine shown in the study now makes it difficult to justify a comparison with oral morphine. (d) Reasons for not using intra-venous morphine as the comparator Some correspondents were surprised that intra-venous morphine was not used as a comparator and Professor Larkin commented that nasal diamorphine "is unlikely [to] replace IV opiates yet". We agree with Professor Larkin. Intra-venous opiates are undoubtedly the gold standard in terms of analgesic efficacy. However, on presentation to the emergency department, the child is in pain and frightened and, in these circumstances, obtaining intra-venous access is difficult, more time consuming than giving intra-muscular morphine and stressful to the child. Fluid resuscitation or emergency anaesthesia are the only absolute indications for immediate intra-venous access, hence the exclusion of these groups. (e) Compliance with ICH Guidelines and issues concerning reconstitution of nasal diamorphine and drug delivery A ready-to-use nasal spray was not used because aqueous solutions of diamorphine HCl are not stable over time. The freeze-dried diamorphine hydrochloride and diluent for reconstitution were supplied in ampoules. Stability data were generated and supported 3 year and 2 year shelf lives respectively. Commercially available nasal dosing devices that delivered 0.1ml were also provided. Accuracy of delivery was determined by shot weights to be within standard acceptable limits of +/-5%. The reconstituted diamorphine solution was shown to be pure and not to degrade for a period of at least 2 hours which amply exceeded the time necessary for reconstitution and dosing the patient. Data to support all the above statements were supplied to the Medicines Control Agency in support of the Clinical Trials Exemption under which the trial was undertaken. All ICH Guideline requirements for Manufacturing, Packaging, Labelling, and Coding Investigational Product(s) were adhered to and manufacture complied with Good Manufacturing Practice. The dose was 0.1 mg/kg and the dosage volume was 0.1ml for all patients. As the patients varied in weight from 14 to 62 kg, it was necessary to reconstitute the diamorphine powder in a specific volume of diluent for each individual child in order to achieve a concentration that would deliver a 0.1mg/kg when dosed to the patient. The reconstitution procedure was simplified by provision of a table linking patient weight with diamorphine ampoule size and volume of diluent. After weighing the patient the relevant volume of diluent was added to the selected ampoule of diamorphine (30mg or 100mg) using syringes fitted with green needles (5ml size for volumes of whole ml and 1ml size for volumes of less than 1ml). Diamorphine is instantly and totally soluble at all the concentrations required to cover the whole weight range. The total volume of reconstituted diamorphine solution was transferred to the nasal dosing device using the syringe. This did not need to be accurate as the desired concentration had already been achieved. This operation was merely a transfer to enable the drug solution to be delivered to the patient using the nasal spray. The nasal dosing device was primed before use by depression of the plunger at least 5 times. Correct use of the nasal device was demonstrated to all staff and instructions given on the importance of holding the device in an upright position. It was quite straightforward to lift the head of any reclining patient sufficiently to achieve dosage with the nasal dosing device in the upright position. The most conveniently positioned nostril was used. The volume of 0.1ml has been shown to be small enough to ensure that leakage down the back of the throat is negligible and does not cause congestion. The diluent was buffered to reduce the acidity of reconstituted diamorphine. It was shown to have a pH of 5.2 and an osmolality ranging from 235 mOsm/kg for a 1.8% solution to 314.3 mOsm/kg for a 3.8% solution. This range ensured that the osmolality was physiological across the whole concentration range (given that normal saline has an osmolality of 290 mOsm/kg). Viscosity was not measured because it was obvious from the constituents of the diluent and the minute amount of diamorphine that the solution was "essentially aqueous". It is unlikely that a single administration of such a minute volume of diamorphine solution could have caused irritation as a result of acidity, when the solution had a pH of 5.2. Nasal irritation is a known side effect of opiates such as pethidine. Of course, intra-muscular injection of morphine can also cause irritation and there was no difference between groups in the number of children who displayed irritation at the 'site of dosage'. It was not deemed relevant to inspect the mucosal status given the short duration of the study (30 minutes for each patient). This might be a relevant observation if nasal diamorphine were to be given repeatedly for another indication. (f) Susceptibility of the trial to bias The issue of the 'convenience' sample is discussed in the paper, where we also acknowledged that a lack of blinding may have introduced bias. We reported children's self-rated pain scores because these were least likely to be biased, an assertion that is supported by the parallel changes in oxygen saturation. Pain ratings by parents and staff also paralleled those of the children themselves but could not be reported because of a lack of space. They are available on request from the authors; a statement to this effect was removed by the journal editors at the editorial stage. Inter-observer agreement data are not relevant to the main objective of the study. Norbert Klocker specifically asked why a double dummy design was not used, i.e. giving all children both the nasal and intra-muscular interventions with one being a placebo according to the randomised treatment allocation. At the outset, equivalence of nasal diamorphine and intra-muscular morphine with respect to analgesic effectiveness was considered sufficient to prefer the former (providing nasal diamorphine was found to be safe), given the poor tolerance of children to the latter. Using a double-dummy design would have prevented us from collecting data on patients' reactions and acceptability to treatment in the trial (which supported the prior view of children's intolerance to this method of treatment). Given this prior view, the view of ethics committees about a double-dummy design was not formally sought, although nursing and medical staff in participating centres considered it to be unethical. (g) Statistical issues Chi-squared tests for trend were used for ordinal pain scores. t- tests were only used to compare the times at which observations were made in the two groups (see footnote to Table 2). In practice, the times at which 'nominal' 5, 10, 20 and 30 minute observations were made varied quite considerably, depending on the minute-by-minute availability of the nurse designated to make the observation. Nevertheless, the similarity of the mean times for each observation for the two groups shows that bias was not introduced by this variation. (h) Concerns about safety and the ethics of using nasal diamorphine Our reporting of complications, described as serious vs. non-serious and sub-classified as mild, moderate or severe, is in accordance with Good Clinical Practice guidelines. Again, additional data on all complications and physiological data are available on request. Claudius Rudin and Axel Schnuch raise ethical issues in using "heroin" in children, and describe their concerns in rather emotive language ("sniffing heroin"). Theo Fenton points out that heroin is a Bayer brand name, and that diamorphine (in this case provided by CP Pharmaceuticals) is used extensively in Britain for the control of acute pain in different clinical settings; consequently, this is a drug with which British doctors have a great deal of experience. This study was reviewed by all of the appropriate local research ethics committees for the 8 hospitals involved (which included a dedicated paediatric emergency department) and a multicentre research ethics committee, and no concerns were raised regarding the use of diamorphine. This particular indication for diamorphine is for single use in a paediatric population and concerns regarding abuse are, therefore, inappropriate. Dr JM Kendall MD MRCP DIMC FFAEM Dr BC Reeves
Dr VS Latter
(1) Multicentre Randomised Controlled Trial of Nasal Diamorphine for analgesia in children and teenagers with clinical fractures. Jason M Kendall, Barnaby C Reeves and Victoria S Latter BMJ 2001;322:261-265 |
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James Robert Craig, SPR anaesthetics Poole General Hospital
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Editor – The intranasal route for the administration of analgesia appears to have great potential and the study by Kendal et al 1 should encourage its use. However their comparison of intramuscular morphine with intranasal diamorphine was pharmacokinetically flawed. The primary problem was their interpretation of the data presently available regarding the bioavailability of intranasal diamorphine. They have assumed it to be 100% based on work by Cone et al,2 which reports that the pharmacokinetic profiles of intranasal and intramuscular diamorphine are equivalent. In contrast to this assumption Cone et al in the same study, estimate that the potency of the intranasal route is approximately 50% that of the intramuscular. This is supported by a second study in which Skopp et al 3 looked at circulating levels of morphine–3- glucuronide following intramuscular and intranasal administration of diamorphine and demonstrated that about half the amount of diamorphine was available from the intranasal route. This lower bioavailability may be as a result of incomplete absorption, distribution into the oropharynx with subsequent swallowing or hydrolysis of diamorphine as it passes through the nasal mucosa. Both Skopp and Cone used dry powder and clearly administration as a fine solution may result in a different bioavailability. Although intranasal and intramuscular diamorphine have similar pharmacokinetic profiles, with peak plasma levels of diamorphine 2,3, and peak levels of 6-acetyl-morphine 3 (one of the active metabolites) occurring within five minutes this cannot be said of intramuscular morphine. Probably as a result of its poor lipid solubility in comparison to diamorphine, morphine has been reported as requiring up to twenty minutes to achieve peak plasma levels by the intramuscular route.4 Peak plasma levels do not correlate with peak effect, which occurs later following redistribution to effector sites. This again is dependent on lipid solubility and degree of ionisation at plasma pH and for morphine has a half life of approximately 34 minutes.5 These facts mean that comparison between intranasal diamorphine and intramuscular morphine over thirty minutes following administration is not likely to give a good account of overall analgesia. The dose of diamorphine chosen has an estimated potency about half that of the morphine used. Its more rapid onset as judged by pain scores and falling oxygen saturations is accounted for by the differing pharmacokinetic profiles. The authors conclusion that 0.1 mg/kg of intranasal diamorphine provides the same degree of pain relief as 0.2 mg/kg of intramuscular morphine is therefore misleading. If speed of onset were the investigators end point the intravenous route would have made a more appropriate comparator. Regardless of the route of comparator a longer follow up period would have allowed more meaningful assessment of the analgesic efficacy of both dose and route. James R Craig 1. Kendall JM, Reeves BC, Latter VS. Multicentre randomised trial of nasal diamorphine for analgesia in children and teenagers with clinical fractures. BMJ 2001; 322: 261-265 2. Cone EJ, Holicy BA, Grant TM, Darwin WD, Goldberger BA. Pharmacokinetics and pharmacodynamics of “snorted” heroin. J Analyt Toxicol 1993; 17: 327-337 3. Skopp G, Ganssmann B, Cone EJ, Aderjan R. Plasma concentrations of heroin and morphine-related metabolites after intranasal and intramuscular administration. J Anal Toxicol 1997; 21: 105-111 4. Stanski DR, Greenblatt DJ, Lowenstein E. Kinetics of intravenous and intramuscular morphine. Clin Pharmacol Ther 1978; 24: 52-59 5. Upton RN, Semple TJ, Macintyre PE. Pharmacokinetic optimisation of opioid treatment in acute pain therapy. Clin Pharacokinet 1997; 33: 225-244 |
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