Subdural haemorrhage is associated with recent morphine treatment in patients with cancer: A retrospective population-based nested case-control study.

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ORIGINAL ARTICLE

Subdural haemorrhage is associated with recent morphine treatment

in patients with cancer: A retrospective population- based nested

case-control study

Cynthia Wei-Sheng Lee

¹

, Chih-Hsin Muo

²

, Ji-An Liang

^3,4

, Fung-Chang Sung

²

, &

Chia-Hung Kao

^3,5

Introduction

Subdural haemorrhage (SDH), the accumulation of haemorrhaging in the subdural space, is a prevalent neurological

disease [1]. A haemorrhage that occurs in the brain parenchyma or the subdural and subarachnoid spaces is commonly

caused by acute disseminated intravascular coagulation or metastatic tumour and rarely arises from haemolysis induced by the administration of chemotherapy [2].

Since 1986, opioids have continued to be highly effective

in the management of cancer pain and their use is recommended in most treatment guidelines [3]; of these, morphine

is regarded as the ‘gold standard’ [4–7]. However, morphine users have an increased risk of fracture, which may be related to increased risk of falling because of central nervous

system effects such as dizziness [8, 9]. Other adverse effects of opioids include neurovascular complications such as ischaemic stroke or microvascular ischaemic changes [10–13]. A previous study found that morphine-associated strokes in cancer patients are predominantly haemorrhagic rather than ischaemic [14].

Patients with cancer requiring pain alleviation are often

administered morphine; thus, it is crucial to understand

the relationship between morphine use and SDH incidence.

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No epidemiological study has investigated this relationship in Taiwan. To evaluate the potential for morphine-related SDH, this study compared the incidence of SDH in patients with cancer treated with and without morphine by using data from the National Health Insurance Research Database (NHIRD) of Taiwan.

Methods Data source

In Taiwan, health insurance is provided by a single-payer programme established by the Bureau of National Health Insurance. The programme covered over 99% of the population of Taiwan in 2010. The Longitudinal Health Insurance

Database 2000 (LHID2000) and the catastrophic illness patient registry (CIPR) are maintained by the National Health Research Institutes and are components of the

National Health Insurance Research Database (NHIRD), which is derived from the Taiwan health insurance programme.

Medical information recorded in the NHIRD

databases includes inpatient and outpatient claims records, medical treatments and personal information such as sex, birthdate and programme enrolment date for each beneficiary.

The LHID2000 contains a set of one million randomly selected claims from the original records held in the

NHIRD database. Diseases were classified according to the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). This study was approved by the ethical review board of China Medical University Hospital.

Study subjects and key variables

A population-based nested case-control retrospective analysis was conducted using the LHID2000. A malignancy cohort

was set up of 25 322 patients newly diagnosed with malignancy (ICD-9-CM 140–208) during 1998–2009 who had not

received morphine treatment before diagnosis. An SDH group was also established, comprising 200 patients with cancer who subsequently developed SDH (ICD-9-CM 432.1, 852.2 and 852.3). The date of SDH diagnosis was assigned as the

index date. Control-group patients were selected from malignancy

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cohort members who had not developed SDH and were frequency matched to SDH cases at a ratio of _4:1 for age, sex, year of malignancy diagnosis and index year.

The key variables identified in this study included

morphine use and SDH-associated comorbidities such as dyslipidemia (ICD-9-CM 272.0–272.4), diabetes (ICD-9-CM

250), coronary artery disease (ICD-9-CM 410–414), hypertension (ICD-9-CM 401–405), cerebrovascular disease (ICD-

9-CM 430–438), atrial fibrillations (AF, ICD-9-CM 427.31), dementia (ICD-9-CM 290.0–290.4 and 331.0) and heart failure (ICD-9-CM 428). These comorbidities were present before the index date. The presence of anticoagulants (warfarin, aspirin, dipyridamole, ticlopidine and clopidogrel) was identified. Morphine use was designated as ‘current’ if the period of the last prescription included the index date or ended within 1 month prior to the index date. If the last prescription ended 1–6 months before the index date, then it was classified as ‘recent’. The last prescription was classified as ‘past’ if it ended more than 6 months before the index date.

Statistical analysis

All statistical analyses were performed using SAS 9.3 for Windows (SAS Institute, Cary, NC) and the level of significance for the two-sided test was p40.05.

Distributions were characterized using a chi-squared test and the t-test and Fisher’s exact test were applied for categorical and continuous variables. Logistic regression methods were applied to estimate odds ratios and 95%

confidence intervals for SDH. The multivariable model was applied to control for age, sex and comorbidity, as shown in Table I. This study assessed the association between SDH and morphine in different malignancies. Attributing risks for SDH in patients with cancer to morphine use were calculated to determine the cause of SDH. This study also estimated the SDH-associated stratum for morphine, including the period and numbers of cumulative days of morphine use.

Results

In this study, 200 SDH and 774 non-SDH malignancy

patient records were selected. The mean age of the SDH

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patients was 71.3 years old (standard deviation¼14.5). The majority of SDH patients were men (67.0% men vs 33.0%

women). It is likely that SDH patients had other

comorbidities or had been treated with anticoagulants, but only cerebrovascular disease showed a significant difference between the SDH and non-SDH groups (15.5% vs 9.95%) (Table I). In total, 35 (17.5%) SDH group and 90 (11.6%) non-SDH group patients received morphine before the index date (Table II). Compared with non-morphine users, morphine users had a 65% greater risk of developing SDH (95% CI¼1.04–2.53). In this assessment of the association between SDH and morphine use for different malignancy types, SDH patients exhibited a significantly greater risk than non-morphine users only for genitourinary malignancy (OR¼2.99, 95% CI¼1.24–7.21) and this effect was

particularly clear for bladder patients with cancer (OR¼18.6, 95% CI¼2.37–146). The attributing risks for SDH in patients to morphine use were 39.4% and 94.6% in cancer overall and bladder cancer, respectively (Table II).

Table III shows the association between SDH and the time difference between the last morphine use and index date.

Compared with non-morphine users, malignancy patients currently using morphine were at the greatest risk (3.08) of developing SDH, followed by recent use (2.58) and past use (1.03) (95% CI¼1.27–5.39, 1.23–5.39 and 0.56–1.89, respectively). Because malignancy patients who received morphine within 6 months prior to the index date had significantly different risks from other groups, this study calculated the cumulative days of morphine use within this period. Compared to patients who did not receive morphine within 6 months prior to the index date, the risk for SDH increased as the number of days of morphine use increased (p¼0.0008 for the trend test, Table IV). Discussion

These results associated recent morphine use with increased

incidence of SDH in patients with cancer. The risk of SDH

increased as the duration of morphine treatment increased

only in patients with cancer treated with morphine within the

previous 6 months.

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Metastatic neoplasms have been found to be associated

with subdural haematomas [15]. However, there is no accurate ICD-9-CM code for brain metastases, so the authors were unable to demonstrate whether SDH is associated with brain metastases using the NHIRD. Early studies have reported that the incidence of brain tumour with a haemorrhage was 3.5% in Taiwan [16] and 2.3% in Japan [17], whereas the occurrence of metastatic tumour with a haemorrhage was 9.3% in Taiwan [16] and 14% in the US [18]. Intracranial

haemorrhaging associated with a metastatic tumour frequently occurs with choriocarcinoma, melanoma, lung neoplasm

and hypernephroma [18]. In contrast, metastatic

hepatocellular carcinoma and papillary thyroid carcinoma occurred with a high incidence of tumour haemorrhaging in a patient cohort in southern Taiwan [16]. The analysis showed that genitourinary patients with cancer treated with morphine have a 2.99-fold (95% CI¼1.24–7.21) greater risk of

developing SDH than patients not receiving morphine treatment do; the increased risk of SDH from morphine treatment

is most prominent in bladder patients with cancer (OR¼18.6, 95% CI¼2.37–146) (Table II). Because the case number of SDH patients was low (n¼35), additional large-scale

investigations are required to determine whether genitourinary patients with cancer receiving morphine treatment are

more susceptible to SDH.

The criteria for selecting analgesics for the elderly include overall efficacy, side-effect profile, onset of action, drug interactions, abuse potential and the severity and type of pain that a patient is experiencing [19]. All opioids are considered effective in cancer pain management, but no studies that specifically address elderly patients with cancer are available [19, 20]. Orally administered morphine is generally used for administering therapy for moderate-to-severe cancer pain;

however, it presents adverse effects including constipation,

nausea and vomiting, vertigo and somnolence [21]. In this study, the observed increased risk of SDH in morphine

users may result from the increased risk of falling, head injury

and subsequent SDH because of central nervous system

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effects such as vertigo.

The strengths of this study include the use of populationbased data, rather than data that is obtained from selfreported drug use and the evaluation of NHIRD records.

However, the study’s limitations are as follows: First, the NHIRD lacks crucial data such as detailed demographic information on smoking habits, alcohol consumption, body mass index, socioeconomic status and family history of systemic diseases. These are all potential risk factors for SDH development and each factor is indirectly associated with morphine use. Therefore, this study was unable to correlate the increased morphine dosage with inactivity or malnutrition or both, because the NHIRD

does not provide records of lifestyle data. However, because the NHIRD covers a highly representative sample of

Taiwan’s general population and because the insurance reimbursement policy is universal, these factors are unlikely to have affected morphine prescription allotment within the study cohort.

Second, because cancer pain might influence mobility

and muscle strength, a nested case-control approach was used to eliminate cancer-related confounding factors. However, evidence derived from a nested case-control study is generally of lower quality than that obtained from randomized trials.

This is because a nested case-control study design is subject to several biases that stem from adjustments made for confounding variables. Thus, despite this study’s meticulous design to adequately control for confounding factors, a potential key limitation is that a bias may remain if unknown confounders are present.

Third, diagnoses recorded in national health insurance (NHI) claims records are primarily used for administrative billing purposes and were not verified for scientific purposes.

The authors were unable to contact patients directly to

inquire about their morphine use, because all records listed

in the NHIRD are anonymous. This study was also unable to

consider morphine prescriptions issued before 1996, which

may have led to an under-estimation of cumulative dosages

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and may have subsequently weakened the observed association.

However, the data obtained on morphine prescription and SDH diagnosis were reliable.

Fourth, there is no accurate ICD-9-CM code for

brain metastases, so one was unable to demonstrate whether SDH is associated with brain metastases using the NHIRD.

The results indicate that SDH incidence is associated with current morphine treatment. However, the effects of morphine appear to be reversible because this relationship was not observed in patients who ceased morphine use more than 6 months before the study index date. Further large population- based studies or large-scale randomized clinical trials

are required to confirm these findings before any definitive conclusions can be drawn. Although the risk of SDH

development diminishes 6 months after morphine treatment has ceased, patients with cancer currently under morphine administration should be monitored to reduce the short-term risk of developing SDH.