Potential Opioid-Sparing Effect of Regular Benzodiazepines in Dyspnea: Longer Duration of Studies Needed
Article Outline
To the Editor:
Navigante et al.1 are to be commended for their excellent study comparing rapid titration and short-term efficacy of oral midazolam vs. oral immediate-release morphine solution. It is an intriguing design using rapid titration in an outpatient clinic and basing the calculation of the fourth hourly dose on this for both medications.
The study is based on the premise that rapid titration (up to three doses in one hour, with final measurement at 90 minutes) to an adequate response (50% reduction over baseline) is an adequate predictor of the dose that will be needed in steady-state. Although the pharmacokinetics of both medications are similar, given that the mechanisms of action in dyspnea are not well defined, it may be that this premise does not allow adequate comparison.
Of note, it is difficult to operationalize the important findings of this study, as the actual doses for each medication in steady-state are not shared with readers. More importantly, the number of breakthrough doses is only dichotomized as ≥1 or none. As such, what is reported is the number of people who have one or more dose(s) of a breakthrough drug, rather than the absolute number of breakthroughs in each arm, which would be a more useful comparison.
It will be interesting in future work to consider whether there is tachyphylaxis to the effects of midazolam on dyspnea in the longer term, given that it is not clear whether its mechanism of action is because of its anxiolytic effect or some other pathway. It also would be interesting in refining this trial design for future similar studies to consider a readjustment of the fourth hourly dose after 24 or 48 hours in a way that accounts for breakthrough utilization.
Generalizing new evidence into palliative care requires careful description of the study population so that providers can assess how applicable new data are to the patients for whom they normally care.2 Navigante et al. provide an elegant depiction of the population in terms of dyspnea etiology (Fig. 2 in their article). Importantly, the population was severely dyspneic, with mean dyspnea numerical rating scale (0–10) scores of 8.7–8.8 (standard deviation 0.3). This compares with median levels of breathlessness in the systematic review by Jennings et al.,3 and the only adequately powered randomized controlled trial exploring the role of opioids in breathlessness (approximately 50
mm on a 100 mm visual analog scale).4 Survival is unknown, and it is not possible to assess how close these individuals were to death. Applicability of these study results to moderately dyspneic patients is unclear, and given the questions of tachyphylaxis and immediate anxiolytic effects, the role of midazolam as the primary dyspnea intervention for ongoing dyspnea management remains uncertain.
This study strongly supports the need to compare opioids with benzodiazepines head to head to establish their roles in this population setting. With that clearly defined, this article also suggests that we should be thinking about the use of low-dose benzodiazepines as an adjunct to regular low-dose sustained-release morphine in the relief of dyspnea, acting essentially as opioid-sparing agents. Most importantly, continued work to define optimal pharmacological management of dyspnea is likely to continue to lead to improved patient outcomes.
References
- . Morphine versus midazolam as upfront therapy to control dyspnea perception in cancer patients while its underlying cause is sought or treated. J Pain Symptom Manage. 2010;39:820–830
- . A framework for generalizability in palliative care. J Pain Symptom Manage. 2009;37:373–386
- A systematic review of the use of opioids in the management of dyspnoea. Thorax. 2002;57:939–944
- Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. BMJ. 2003;327:523–528
PII: S0885-3924(10)00538-5
doi:10.1016/j.jpainsymman.2010.07.002
© 2010 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.
Refers to article:
- Morphine Versus Midazolam as Upfront Therapy to Control Dyspnea Perception in Cancer Patients While Its Underlying Cause Is Sought or Treated
