Omata Rina, Asami Akane, Hara Azusa, Urushihara Hisashi
Division of Drug Development and Regulatory Science, Faculty of Pharmacy, Keio University, 1-5-30, Shibakoen, Minato-ku, Tokyo, Japan.
Drugs Real World Outcomes. 2024 Sep;11(3):529-540. doi: 10.1007/s40801-024-00446-x. Epub 2024 Aug 8.
Gabapentinoids (GBP) and benzodiazepines (BZ) are commonly prescribed in older adults and their package inserts list edema and vertigo as adverse drug reactions. These adverse drug reactions may be treated with symptomatic drug therapies without discontinuing the culprit drugs or decreasing their dose, thereby initiating a prescribing cascade and often resulting in polypharmacy. Whether prescribing cascades occur in the treatment of edema and dizziness among Japanese patients treated with GBP and BZ has not been investigated, including treatment with mirogabalin, a class drug of GBP marketed in Japan.
We aimed to investigate prescribing cascades with GBP-induced and BZ-induced edema and dizziness treated with loop diuretics (LD) and anti-vertigo drugs (AVD), respectively, among older adults.
A prescription sequence symmetry analysis design was used to detect signals of prescribing cascades associated with edema and dizziness induced by GBP and BZ (exposure drugs). Loop diuretics and AVD were the outcome drugs used to identify prescribing cascades following the initiation of exposure drugs. The study population consisted of enrollees of a large-scale health claims database provided by DeSC Healthcare, Inc., between April 2014 and March 2021. Subjects eligible for a prescription sequence symmetry analysis were patients aged ≥ 65 years prescribed an outcome drug within 90 days before and after exposure drug initiation. A signal of a prescribing cascade was detected if secular trend-adjusted sequence ratios were statistically significant on comparison of the frequencies of outcome drug initiation before and after exposure drug initiation.
We identified 2671 patients with prescriptions of a GBP-LD combination, 4009 with a GBP-AVD combination, 8675 with a BZ-LD combination, and 9462 with a BZ-AVD combination. The adjusted sequence ratios for GBP-LD and BZ-LD cascades were significantly larger than one (adjusted sequence ratio [95% confidence interval], 1.69 [1.56-1.83]; 1.35 [1.29-1.41], respectively), indicating positive signals of prescribing cascades. No signal was detected for the GBP-AVD or BZ-AVD cascade (0.89 [0.83-0.94]; 0.90 [0.87-0.94], respectively). The adjusted sequence ratio for the mirogabalin cascade was higher than that for pregabalin (2.23 [1.84-2.71] vs 1.59 [1.46-1.73]).
Our study provides good evidence that LD-prescribing cascades associated with edema would be a class effect of GBP and BZ. Edema emerging around 1 month after GBP initiation should be carefully differentiated from pathological edema, and undue LD prescription as a prescribing cascade should be avoided.
加巴喷丁类药物（GBP）和苯二氮䓬类药物（BZ）在老年人中常用，其药品说明书将水肿和眩晕列为药物不良反应。这些药物不良反应可用对症药物治疗，而无需停用致病药物或降低其剂量，从而引发处方级联反应，并常常导致多重用药。在接受GBP和BZ治疗的日本患者中，在水肿和头晕的治疗中是否会出现处方级联反应尚未得到研究，包括在日本上市的GBP类药物米罗加巴林的治疗情况。
我们旨在调查在老年人中，分别用袢利尿剂（LD）和抗眩晕药物（AVD）治疗GBP和BZ引起的水肿和头晕时的处方级联反应。
采用处方序列对称性分析设计来检测与GBP和BZ（暴露药物）引起的水肿和头晕相关的处方级联反应信号。袢利尿剂和AVD是用于识别暴露药物开始使用后处方级联反应的结局药物。研究人群包括2014年4月至2021年3月期间由DeSC Healthcare公司提供的大规模健康索赔数据库的登记人员。符合处方序列对称性分析条件的受试者为年龄≥65岁、在暴露药物开始使用前后90天内开具结局药物处方的患者。如果在比较暴露药物开始使用前后结局药物开始使用的频率时，经长期趋势调整的序列比具有统计学意义，则检测到处方级联反应信号。
我们确定了2671例开具GBP-LD组合处方的患者、4009例开具GBP-AVD组合处方的患者、8675例开具BZ-LD组合处方的患者和9462例开具BZ-AVD组合处方的患者。GBP-LD和BZ-LD级联反应的调整序列比显著大于1（调整序列比[95%置信区间]分别为1.69[1.56-1.83]；和1.35[1.29-1.41]），表明存在处方级联反应的阳性信号。未检测到GBP-AVD或BZ-AVD级联反应的信号（分别为0.89[0.83-0.94]；0.90[0.87-0.94]）。米罗加巴林级联反应的调整序列比高于普瑞巴林（2.23[1.84-2.71]对1.59[1.4,6-1.73]）。
我们的研究提供了充分的证据，表明与水肿相关的LD处方级联反应是GBP和BZ的类效应。在GBP开始使用后1个月左右出现的水肿应与病理性水肿仔细鉴别，并应避免作为处方级联反应的不适当的LD处方。
