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Article
Issue:
Vol 66 Issue 2 (February 2011)
Article title:
Use of invasive placebos in research on local anaesthetic interventions 
Author(s):
S. McGuirk, C. Fahy, D. Costi, A. M. Cyna 

Placebo blocks in local anaesthesia studies: the need for balance

Last post 17 Mar 2011, 9:30 AM by Cyna Allan. 1 replies.
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  •  25 Feb 2011, 11:29 AM 736

    Placebo blocks in local anaesthesia studies: the need for balance

    I read the recent article by McGuirk et al [1] with interest and some concern. The authors raise the issue of the appropriateness of the use of an ‘invasive’ placebo group in local anaesthetic studies. The authors do make a number of important points. Investigators are required to carefully consider the need for an invasive placebo intervention, and to take steps to minimise the potential for harm. Researchers must use the least invasive placebo approach that achieves the objectives of blinding the patient, the assessor and other healthcare providers to the group allocation. Invasive placebo controls should only be used, when no other study design will yield the requisite data. Unfortunately, their potentially useful contribution to this debate was undermined by the rather unbalanced manner in which they approached this complex issue.

    The implications for clinical research of the Declaration of Helsinki [2] for clinical research are significant. In essence, any randomised clinical trial could be considered to be in breach of individual provisions of this declaration. The apparent conflict arises from the fact that the aim of any study is to answer questions about groups of patients, rather than providing care to the individual patient [3]. However, taken together, the provisions of the Declaration of Helsinki provide a strong justification for clinical research, while highlighting the need to safeguard the individual study patient. The justification for clinical studies stems from the potential value of the knowledge to be gained for the general population [3]. Ethical clinical research must balance commitments to rigorous science, with the protection of research subjects from undue risks of harm or exploitation. The quality of consent process is of paramount importance. The patient must be properly informed of the risks of both the active and placebo interventions, be made aware that they may receive either intervention, be informed that they are unlikely to benefit directly, but that the study should provide information that will improve the management of similar patients in future.

    Are there situations where there are a sufficient scientific justification to use an ‘invasive’ placebo? Firstly, no research procedure, even one as simple as venepuncture, is without some risk  [4]. When understood in these terms, there is no difference in principle between invasive placebos and a venepuncture for  research purposes [3]. What differs between these research interventions is the likelihood of risk of an adverse event occurring. The rationale for using a placebo group, where no alternative treatment exists, is to minimise the potential for bias and enhance study validity. Where no suitable alternatives exist, and where the risk to the patient is minimised, then invasive placebos can be justified. In their careful consideration of these issues, the Report of the Council on Ethical and Judicial Affairs of the American Medical Association on Surgical ‘Placebo’ Controls recognise that the use of a placebo procedure that could cause harm, without offering a compensating benefit, may pose ethical problems and may be considered to violate the principle of non-malfeasance [5]. However, they balance this concern by recommending specific patient safeguards and strictly limiting the use of placebo controls. They cite examples in the literature of procedures that were considered effective until disproven in a clinical study. An example is internal mammary artery ligation, used in the 1950s in patients with myocardial ischaemia. A subsequent study found the procedure no more effective than an incision without ligation [6]. It is difficult to see how this and other similar results could have been demonstrated without the use of an invasive placebo group.

    There are a number of specific issues regarding the methodology of the study by McGuirk et al. While I do understand the wit, the ‘SHAM’ grading scale does not measure ‘serious harm and morbidity’. The authors assign a grading of 1 out of a scale of 4 on the SHAM scale to a skin reaction to skin preparation. It is difficult to see how a temporary skin reaction to skin preparation constitutes serious harm and morbidity. Similarly, does a superficial haematoma warrant a grading of 2 on a 4 point scale of serious harm and morbidity? The scale lacks precision. The definition of a category 4 SHAM event lacks any appreciation of the frequency of a particular risk. Grade 4 appears to include all procedures with any risk of major complications, regardless of the size of that risk. As discussed earlier, this category could include venepuncture [4]. The deficiencies of the SHAM scale are revealed in Table 4, where the authors attribute a SHAM grade 4 to a patient that suffered a temporary subcutaneous bruise of less than 1cm in diameter at the injection site [7]. They also grade temporary erythema at the injection site as a grade 4 event [8].

    Of concern is the authors’ attributing the finding of reduced sensation in a patient following hip fracture to a placebo fascia iliaca block [9]. No evidence is presented in the original paper to support this assertion. It is much more likely that this nerve injury occurred at the time of the hip fracture, and not due to the placebo fascia iliaca block. The authors also state that this sensation loss was permanent. Again, there is no evidence to support this assertion, as sensation was only assessed at 30, 60, and 180 minutes after the procedure [9]. The reasons for these apparent errors are not clear. Perhaps they demonstrate the fact that it is possible for three authors to agree in their misclassification of an event. It is reassuring that no patient in the  fifty-nine studies examined suffered serious permanent injury as a result of a placebo block. For some reason, these important finding does not appear in the results section of the manuscript.

    The authors cite two studies performed by our research group, which investigated the efficacy of the transversus abdominis plane (TAP) block in patients undergoing total abdominal hysterectomy [10] and caesarean delivery [11]. Patients in both studies were randomly assigned to a landmark guided TAP block with local anaesthetic or to a similar procedure with saline. The risks of a TAP or placebo block were clearly explained to the patients, they were given information in writing regarding the complication risks, and they freely consented to participate. We considered the placebo TAP block to be justified as it reduced the potential for bias, and the risk to patients was very low, as evidenced by the fact that our group had performed several hundred such blocks without complication. In fact, no patient in any of our TAP studies, in either the placebo or treatment group has experienced permanent or transient harm as a result of the block. While we have subsequently become aware of a report of liver damage following a landmark TAP block [12], it is very difficult to see how this could happen if the correct landmarks are used for this approach, given the posterior location of the injection site.

    In conclusion, the efforts of McGuirk et al in raising this important issue are welcome. The need for careful and balanced debate regarding the use of invasive placebo blocks is clear. The limitations of the study McGuirk et al are regrettable, and serve to detract from this serious issue.

    John Laffey

    National University of Ireland and Galway University Hospitals,

    Galway,

    Ireland.

    Email: john.laffey@nuigalway.ie

     

    No external funding and no competing interests declared

     

    References

    1. McGuirk S, Fahy C, Costi D, Cyna AM Use of invasive placebos in research on local anaesthetic interventions. Anaesthesia 2011; 66: 84-91.
    2. World Medical Association. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects, 2008. http://www.wma.net/en/30publications/10policies/b3/17c.pdf. (accessed 22/02/2011).
    3. Miller FG, Kaptchuk TJ Sham procedures and the ethics of clinical trials. J R Soc Med 2004; 97: 576-8.
    4. Galena HJ Complications occurring from diagnostic venipuncture. J Fam Pract 1992; 34: 582-4.
    5. American Medical Association. Report of the Council on Ethical and Judicial Affairs: Surgical "Placebo" Controls. Report 3-A-00. http://www.ama-assn.org/ama1/pub/upload/mm/code-medical-ethics/2076a.pdf. (accessed 22/02/2011).
    6. Cobb LA, Thomas GI, Dillard DH, Merendino KA, Bruce RA An evaluation of internal-mammary-artery ligation by a double-blind technic. New England Journal of Medicine 1959; 260: 1115-8.
    7. Belavy D, Cowlishaw PJ, Howes M, Phillips F Ultrasound-guided transversus abdominis plane block for analgesia after Caesarean delivery. British Journal of Anaesthesia 2009; 103: 726-30.
    8. Takmaz SA, Uysal HY, Uysal A, Kocer U, Dikmen B, Baltaci B Bilateral extraoral, infraorbital nerve block for postoperative pain relief after cleft lip repair in pediatric patients: a randomized, double-blind controlled study. Annals of Plastic Surgery 2009; 63: 59-62.
    9. Foss NB, Kristensen BB, Bundgaard M, et al. Fascia iliaca compartment blockade for acute pain control in hip fracture patients: a randomized, placebo-controlled trial. Anesthesiology 2007; 106: 773-8.
    10. 10.  Carney J, McDonnell JG, Ochana A, Bhinder R, Laffey JG The transversus abdominis plane block provides effective postoperative analgesia in patients undergoing total abdominal hysterectomy. Anesthesia & Analgesia 2008; 107: 2056-60.
    11. 11.  McDonnell JG, Curley G, Carney J, et al. The analgesic efficacy of transversus abdominis plane block after cesarean delivery: a randomized controlled trial. Anesthesia & Analgesia 2008; 106: 186-91.
    12. 12.  Farooq M, Carey M A case of liver trauma with a blunt regional anesthesia needle while performing transversus abdominis plane block. Reg Anesthesia and Pain Medicine 2008; 33: 274-5.
  •  17 Mar 2011, 9:30 AM 771 in reply to 736

    Re: Placebo blocks in local anaesthesia studies: the need for balance

    We thank Dr. Laffey for his interest in our study but, cannot agree that our paper was "rather unbalanced". This perception probably stems from the lack of almost any previous reasonable discussion regarding the ethics of using invasive local anaesthetic ‘placebo’ procedures.[1] Our investigation showed that several studies were using invasive ‘placebo’ controls to achieve blinding of patient and outcome assessors without any apparent consideration of a non-invasive alternative.[2] Whilst we agree that ethical clinical research must balance commitments to rigorous science, we question whether it is good science to call an invasive procedure "a placebo" as discussed in the accompanying editorial to our paper.[3] We also agree that the quality of the consent process is of paramount importance. However, it is likely that many patients will not understand the full implications of participating in a study and will trust their doctor or researcher to do the right thing ethically by not placing them at unnecessary risk. As stated in our paper [2] and in the accompanying editorial, [3] the use of invasive controls have the potential to cause serious complications and are not simply a pharmacologically inert ‘placebo’ pill.  We agree with Dr Laffey’s statement that, "invasive placebo controls should only be used, when no other study design will yield the requisite data". However research groups frequently fail to report that any other possible, less invasive controls are considered. Indeed, Dr Laffey states that the invasive ‘placebo’ TAP blocks used by his group [4,5] reduced the potential for bias, and the risk to patients was very low. He then states that, it is difficult to see how a liver laceration using his approach to TAP can occur. The fact remains that it did occur.[6] We suggest that, blinding of patient and outcome assessor can frequently be achieved using less invasive Grade 0-2 SHAM techniques and, the risk of invasive TAP controls are unnecessary and ethically unacceptable. For example, TAP control group patients can have the same preparation as the intervention group without skin penetration, – i.e. the site of the block can be prepared with antiseptic and draped, ultrasound utilised to identify nerves, the skin indented with a blunt cannula, and any other manoeuvre performed as necessary to mimic the intervention non-invasively.  Any dressings can then be placed over the site in control patients as they are in the TAP group. This process would confer on control group patients a SHAM 1, rather than a SHAM 4, risk and yet still allow for a double blind study design without exposing control participants to an invasive procedure. 

    As Dr Laffey rightly points out, the SHAM scale does not take into account risk frequency. Indeed we gave this considerable thought when designing the scale and recognise that probability of occurrence is relevant. However, so too is the nature of the risk and we suggest that Dr Laffey’s claim that, "there is no difference in principle between invasive placebos and a venepuncture for research purposes" is a little bold. More importantly as stated above, can double blinding be achieved in a non-invasive way that eliminates or minimises potential risk? One interesting claim Dr Laffey does make is that, "the scale lacks precision". Unfortunately, this is inevitable given that in part, risk has a normative component. Hence, what is an unacceptable risk to some may not be for others and, we recognise that getting complete agreement on the substance of our scale will be difficult. This is a general problem with defining risk and is the current focus of further research currently underway at our institution.

    The "number of specific issues regarding the methodology" and the "apparent errors" of our study seem to have arisen from Dr Laffey’s misreading of our paper and misinterpretation of the results. SHAM is a risk scale representing a range of morbidity from none to serious harm. Dr Laffey appears to have misunderstood the findings reported in Table 4 of our paper [2] where actual complications that occurred in control group patients are reported. Perhaps the labelling of this table could have been clearer. The temporary, subcutaneous bruise of less than 1cm in diameter at the injection site in the TAP study control group patient referred to by Dr Laffey [7] was not graded as a SHAM 4 complication.  It was the TAP saline intervention, which all control group patients received, that was graded as SHAM 4 as there was also a risk of bowel perforation, liver laceration, and other organ damage. Similarly, the “temporary erythema” at the injection site referred to, was a complication reported in a control group patient previously assessed to have a SHAM Grade 4 control intervention. This control patient received an infra-orbital injection of saline, a procedure which has recently been reported to risk globe penetration.[8]

    Dr Laffey suggests that the finding of reduced sensation in a patient following hip fracture to an invasive placebo fascia iliaca block [9] is much more likely to have occurred as a result of nerve injury at the time of the hip fracture or during surgery. However the fact that an invasive 'placebo' fascia iliaca block was administered makes it impossible to exclude the invasive control intervention as the cause. Dr Laffey also questions the grading of temporary and permanent. We defined as permanent, any complication that was reported by authors not to have resolved when the study ended. Perhaps better terms would have been ‘persistent’ or ‘unresolved’. Dr Laffey also questions why we did not report the absence of serious permanent injury as a result of a placebo block in the results section of the manuscript. Perhaps we should have, but at least one study reported a persistent, unresolved complication in a patient allocated to an invasive placebo block.[9]

    In conclusion, we appreciate the opportunity to address the concerns Dr Laffey has raised. We agree with him that careful and balanced debate regarding the use of invasive placebo blocks is long overdue. We hope that a careful read of our paper [2] and the accompanying editorial [3] will help provide some balance to this serious issue.

    Allan M Cyna

    Cormac Fahy

    David Costi

    Sinead McGuirk

    Women’s and Children’s Hospital

    Adelaide 

     

    Email:  allan.cyna@health.sa.gov.au 

    No external funding and no competing interests declared

     

    References

    1. Ghai B. Subtenon block compared to intravenous fentanyl for perioperative analgesia in pediatric cataract surgery. Anesthesia & Analgesia 2009; 109: 1349–50.
    2. McGuirk S, Fahy C, Costi D, Cyna AM. Use of invasive placebos in research on local anaesthetic interventions. Anaesthesia 2011; 66: 84-91.
    3. Sites BD, Neal JM. Placebo or Intervention? Is it all a SHAM. Anaesthesia 2011; 66: 73-75.
    4. Carney J, McDonnell JG, Ochana A, Bhinder R, Laffey JG The transversus abdominis plane block provides effective postoperative analgesia in patients undergoing total abdominal hysterectomy. Anesth Analg 2008; 107: 2056-60.
    5. McDonnell JG, Curley G, Carney J, et al. The analgesic efficacy of transversus abdominis plane block after cesarean delivery: a randomized controlled trial. Anesth Analg 2008; 106: 186-91.
    6. Farooq M, Carey M A case of liver trauma with a blunt regional anesthesia needle while performing transversus abdominis plane block. Reg Anesth Pain Med 2008; 33: 274-5.
    7. Belavy D, Cowlishaw PJ, Howes M, Phillips F Ultrasound-guided transversus abdominis plane block for analgesia after Caesarean delivery. Brit J Anaesth 2009; 103: 726-30.
    8. Saeedi OJ, Wang H; Blomquist PH. Penetrating Globe Injury During Infraorbital Nerve Block. Arch Otolaryngol Head Neck Surg. Published online January 17, 2011. doi:10.1001/archoto.2010.239
    9. Foss NB, Kristensen BB, Bundgaard M, et al. Fascia iliaca compartment blockade for acute pain control in hip fracture patients: a randomized, placebo-controlled trial. Anesthesiology 2007; 106: 773-8.

     

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