Association of intensive morphine treatment and increased stroke
incidence in prostate cancer patients: A population-based nested
case-control study
Running title: Stroke related to morphine in prostate cancer
Cynthia Wei-Sheng Lee, PhD1,2; Chih-Hsin Muo, MSc3,4; Ji-An Liang, MD5,6;
Fung-Chang Sung, PhD3,4; Chia-Hung Kao, MD5,7
1Center for Drug Abuse and Addiction, China Medical University Hospital, Taichung,
Taiwan; 2College of Medicine, China Medical University, Taichung, Taiwan; 3Department of Public Health, China Medical University, Taichung, Taiwan;
4Management Office for Health Data, China Medical University Hospital, Taichung,
Taiwan; 5Graduate Institute of Clinical Medicine Science and School of Medicine,
College of Medicine, China Medical University, Taichung, Taiwan; 6Department of
Radiation Oncology, China Medical University Hospital, Taichung, Taiwan;
7Department of Nuclear Medicine and PET Center, China Medical University
Hospital, Taichung, Taiwan
Cynthia Wei-Sheng Lee and Chih-Hsin Muo contributed equally to this study.
Corresponding author: Dr. Chia-Hung Kao, Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, No. 2, Yuh-Der Road, Taichung 404, Taiwan. Tel: +886 4 22052121x7412; Fax: +886 4
22336174; E-mail: d10040@mail.cmuh.org.tw
ACKNOWLEDGMENTS
The study was supported by grants from the study hospital (101-061 and DMR-100-076); Taiwan Department of Health Clinical Trial and Research Center and for Excellence (DOH102-TD-B-111-004), Taiwan Department of Health Cancer Research Center for Excellence (DOH102-TD-C-111-005); and International
Research-Intensive Centers of Excellence in Taiwan (I-RiCE) (NSC101-2911-I-002-303).
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
All authors declare that they have no conflicts of interest.
AUTHOR CONTRIBUTIONS
Conception and design: Cynthia Wei-Sheng Lee, Chih-Hsin Muo, Chia-Hung Kao Administrative support: Chih-Hsin Muo, Fung-Chang Sung
Collection and assembly of data: Cynthia Wei-Sheng Lee, Ji-An Liang, Chia-Hung
Kao
Kao
Manuscript writing: All authors
ABSTRACT
Background: We address the potential problem of stroke induced by morphine exposure by comparing the incidence of stroke in cancer patients treated with and without morphine.
Materials and Methods: We performed a population-based nested case-control retrospective analysis on the Longitudinal Health Insurance Database 2000 and Registry for Catastrophic Illness Patients of Taiwan. This study is based on a malignancy cohort of 31 611 patients without a history of stroke, and 1208 patients who subsequently developed stroke served as the stroke group. Four controls of matched age, sex, entry year, and entry month for each case were selected from the malignancy cohort top from the non-stroke group. We used logistic regression to estimate the odds ratios and 95% confidence intervals, and applied the multivariable model to control for age, sex, hypertension, diabetes, hyperlipidemia, and
cardiovascular disease.
Results: Cancer patients who received morphine had a 12% higher risk of developing stroke than non-morphine users. However, the difference was non-significant. A significant difference only appears in prostate cancer patients, where morphine users have a 3.02-fold (4.24- and 2.90-fold for hemorrhagic and ischemic stroke,
respectively) higher risk of suffering from stroke. The risk increased significantly as the morphine dosage increased to ≥170 mg/y of treatment.
Conclusion: Intense morphine treatment may be associated with an increased stroke incidence in patients with malignancy, and the association is particularly significant for prostate cancer patients.
Mini-Abstract:
We used the data of the National Health Insurance system of Taiwan and found intense morphine treatment may be associated with an increased stroke incidence in patients with malignancy, particularly significant for prostate cancer patients.
INTRODUCTION
The management of chronic pain is an essential element of the palliative care of cancer patients.1 The overall prevalence of cancer-related pain ranges from 14% to
100%, depending on the specific type of pain and the study population.2 The 3-step
treatment for pain relief proposed by the World Health Organization (WHO) in 1986, which proceeds from non-opioids to weak and then strong opioids as needed, has been suggested to be the most suitable treatment arm in palliative treatment for advanced cancer patients.3 Since 1986, opioids have continued to be a mainstay in the
management of cancer pain in all treatment guidelines,4 and morphine is viewed as
the “gold standard.”5-8 With major advances in oncological therapies, cancer is no
longer a “terminal disease.” More than half of all cancer patients live more than 2 years after diagnosis, and currently, approximately 13.7 and 0.35 million cancer survivors are in the United States9 and Taiwan (unpublished estimation), respectively.
With improved survival rates, the management of chronic pain remains a major challenge in palliative care.
The long-term use of opioids is controversial for many reasons. The primary reason is the psychological addiction, abuse, and diversion of these medications. This
problem is increasing in severity as the availability of opioids increases.10 Heroin is
the most commonly abused morphine derivative, and its abuse is associated with several pathological effects of the central nervous system (CNS). These effects include neurovascular complications such as ischemic stroke or microvascular ischemic changes.11-14 The activation of the prosurvival opioid receptor/PI3K/Akt
neuroprotection.15 Therefore, opioids might play a role in regulating neurovascular
functions through opioid receptor activation.
Morphine is an important analgesic and yet a potent addictive drug. We are curious about the possible negative effects of long-term morphine treatment, especially in cancer patients since they are the largest population treated with morphine
chronically. In this study, we focus our attention on stroke, one of the possible side effects resulted from chronic morphine use, and hypothesize that long-term morphine treatment raises the occurrence of stroke in human populations. Given the increased periods of morphine exposure in cancer patients because of prolonged pain
management, it is imperative to know whether morphine also increases the incidence of stroke. There is no systemic epidemiological study on whether long-term morphine treatment raises the occurrence of stroke in human populations. To address the potential problem of stroke induced by morphine exposure, this study presents a comparison of the incidence of stroke in cancer patients treated with and without morphine using the National Health Insurance Research Database (NHIRD) of Taiwan.
MATERIALS AND METHODS
This population-based nested case-control retrospective analysis is based on the Longitudinal Health Insurance Database 2000 (LHID2000) and Registry for Catastrophic Illness Patients released by the National Health Research Institutes (NHRI). The National Health Insurance (NHI) program covers over 99% of the population of Taiwan. The LHID2000 contains all the original claims data of 1 000
000 persons randomly sampled from the 2000 Registry for Beneficiaries of the NHIRD. This registry contains the registration data of approximately 23.72 million beneficiaries of the NHI program during the period of 1996–2000. The LHID2000 includes all the registration and claims data of these 1 000000 persons collected by the NHI program. The NHRI reported no statistically significant differences in the distributions of age, sex, or health care expenditures between the LHID2000 and the NHIRD. The International Classification of Diseases, 9th Revision, Clinical
Modification was used to record the diagnoses. All data files are coded and linked with scrambled identifications to secure patient privacy. This study was exempted from ethical review.
Data collection
We identified a malignancy cohort of 31 611 patients with newly diagnosed malignancy (ICD-9-CM 140-208) from the Registry for Catastrophic Illness Patients in 1998-2010 and without a history of stroke (ICD-9-CM 430-438) before the date of malignancy diagnosis. Within this cohort, 1208 patients who subsequently developed stroke served as the stroke group, and the date of diagnosed stroke served as the entry date. For the non-stroke group, approximately four controls without stroke from the malignancy cohort were frequency-matched with age (every 5 y), sex, entry year, and entry month for each case. The prescription date of morphine is prior to the diagnosis date of stroke in the cancer patients included in this study. The mean duration from
the beginning of morphine prescription to stroke diagnosis is 2.03 years (SD=2.21 years) with median duration of 1.24 years (0.37-3.06 years, Q1-Q3).
Statistical analysis
We performed all statistical analyses using SAS 9.1 software for Windows (SAS Institute, Cary, NC, USA). We used the χ2 test to determine the differences of the
distribution of age, sex, and comorbidities between stroke and non-stroke groups. Comorbidities included hypertension (ICD-9-CM 401-405), diabetes (ICD-9-CM 250), hyperlipidemia (ICD-9-CM 272.0-272.4), and cardiovascular disease (CVD) (ICD-9-CM 410-414). Comorbidities were identified before the entry date. We used logistic regression to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of stroke, and applied the multivariable model to control for age, sex, hypertension, diabetes, hyperlipidemia, and CVD. We also assessed the effect of stroke on morphine dosage during the treatment period. Dosage was stratified by the quartile dosage (none, 1-21 mg, 22-42, 43-170 and >170 mg/y of treatment). All statistical analyses were two-sided, and the alpha level was set at 0.05.
RESULTS
Among the 1208 stroke patient data collected for this study, 228 patients were shown to have experienced a hemorrhagic stroke (18.9%), and 980 patients experienced an ischemic stroke (81.1%). Men constituted the majority of the stroke group (61.9% vs 38.1%), and the mean age was 69.8 years (SD = 13.2). Compared with the non-stroke group, more patients in the stroke group received morphine (25.8% vs 23.6%), but the difference was non-significant (Table 1). Patients with stroke were more prone to
comorbidities, including hypertension, diabetes, hyperlipidemia, and CVD, compared to non-stroke patients.
Patients with malignancy who received morphine had a 12% higher risk of developing stroke than those who did not received morphine. However, the difference was non-significant (Table 2). We also assessed the risk of stroke based on malignancy subtype. For patients with prostate cancer, those who received morphine had a 3.02-fold higher risk of developing stroke (P < .001) after controlling for age, sex, and comorbidities.
Table 3 shows the ORs of stroke subtypes between the morphine and non-morphine groups. Compared to patients who did not receive morphine, patients who received morphine had a significantly higher risk of hemorrhagic stroke (OR = 1.36, 95% CI = 1.02-1.82), whereas the risk of ischemic stroke was non-significant. In patients with prostate cancer, those who received morphine had 4.24- and 2.90-fold higher risks for hemorrhagic and ischemic stroke, respectively, than those who did not receive morphine. In patients with other types of cancer, the risk of developing either stroke subtype was not significantly higher, compared to patients who did not receive morphine.
Table 4 shows the association between stroke and morphine dosage. Patients who received a high dosage of morphine had a higher risk of both stroke subtypes, but the trend test was non-significant for ischemic stroke. For patients with prostate cancer, stroke risk increased with morphine dosage. The trends were the same for both hemorrhagic and ischemic strokes.
This study shows that morphine use may be associated with an increased stroke incidence in patients with malignancy. The risk increases with morphine dosage, and was most significant in prostate cancer patients who received ≥170 mg/y of treatment. These patients have a 6.09-fold higher risk (P < .01) of developing stroke (Table 4). These unexpected findings may arouse public interest regarding the safety of
morphine use for the pain management of cancer patients.
Morphine is the major metabolite of heroin, a semisynthetic derivative of opium. It binds to the μ-opioid receptor, which is responsible for analgesia, euphoria, nervous system depression, respiratory depression, and constipation. Heroin tends to cause hypotension from decreased peripheral vascular resistance, bradycardia by inhibiting the baroreceptor reflex, and respiratory depression by slowing the brain’s response to high CO2 and low O2 levels.16 Most reported strokes associated with heroin use are
ischemic. Heroin-associated stroke is often caused by cardioembolism in infective endocarditis.17 Arteritis and vasculitis have also been implicated as a cause of
heroin-related strokes. Other potential causes of stroke include hypotension and hypoxemia induced by opiate overdose, resulting in global hypoxic-ischemic injury to vulnerable brain areas.18 This study shows that morphine-associated strokes are mostly
hemorrhagic, instead of ischemic. Therefore, a molecular mechanism unlike that of heroin might underscore the occurrence of stroke in cancer patients treated with morphine.
This study is the first to show that increased morphine dosage is a potential risk factor of stroke in prostate cancer patients after adjusting for age and comorbidity (hypertension, diabetes, hyperlipidemia, and CVD). Prostate cancer is the most common solid neoplasm affecting older men, and therefore, it is a major health concern in developed countries. Androgen deprivation therapy (ADT) may increase
the risk of stroke/transient ischemic attacks in prostate cancer patients. A recent Swedish population-based study demonstrated that, regardless of treatment, men with prostate cancer exhibited a small increase in stroke risk, compared with an age-matched control population. However, the initiation of endocrine treatment is not associated with an increased risk of stroke.25 A 5-year follow-up study in Taiwan
presented a similar conclusion, showing no significant difference in stroke risk between ethnic Chinese patients with prostate cancer who did versus those who did not receive ADT.26 Whether an ADT-morphine interaction results in complications
such as diabetes and stroke requires further analysis.
In our study group, morphine use is always before the incidence of stroke, so stroke is the outcome and not the cause of morphine description. Analysis of the mortality of the stroke patients showed that the morphine group (33.88/100 person-years from stroke date to death) has 40% higher mortality (HR = 1.40, 95 % CI = 1.17-1.68, P < . 001) than the non-morphine group (21.74/100 person-years from stroke date to death). The higher mortality of the morphine group is probably resulted from the severity of prostate cancer (pain relief of bone metastasis in morphine users) instead of the severity and prognosis of stroke.
There are some weaknesses in our study. The cancer patients treated with morphine usually have more advanced stage of disease, less activities of daily living status (a risk factor of thrombus), and more pain. Furthermore, in prostate cancer patients, those treated with morphine usually have more bone metastasis and received more hormonal therapy, a risk of thrombus. In addition, in bedridden patients, we
sometimes use anticoagulant therapy to prevent DVT and pulmonary thrombus; this could be a risk factor of hemorrhagic stroke. These factors should be considered to
conduct well-designed case-control trial to clarify the association of morphine use and stroke incidence in the future.
The strengths of the current study include its use of population-based data and the use of NHIRD records rather than self-reported drug use. However, certain limitations should be mentioned. First, the NHIRD lacked some important data, including
detailed demographic information such as smoking habits (the coding of smoking only occurs when the patient seek help in smoking cessation outpatient service, leading to underestimation of the real smoking prevalence), alcohol consumption, body mass index (not shown in the NHI claim record), socioeconomic status, and a family history of systemic diseases. These may be major risk factors for cancer or stroke, and are indirectly associated with morphine use. However, because the
NHIRD covers a highly representative sample of Taiwan’s general population and the reimbursement policy is universal, these factors are unlikely to affect the prescription of morphine. Second, the evidence derived from a nested case-control study is
generally lower in quality than that from randomized trials. This is because a nested case-control study design is subject to many biases related to adjustments for confounding variables. Despite a meticulous study design with adequate control of confounding factors, a key limitation of this study is that a bias could remain if unmeasured or unknown confounders are present. Third, the diagnoses recorded in the NHI claims primarily serve the purpose of administrative billing, and are not verified for scientific purposes. We were unable to contact patients directly to enquire about their morphine use because all beneficiaries listed on the NHIRD are protected by anonymity. We were also unable to consider morphine prescriptions issued before 1996. This omission could produce an underestimation of the cumulative dosage and
may have weakened the observed association. However, the data on morphine prescription and diagnoses of cancer and stroke were reliable.
The results of this study indicate that intense morphine treatment may be associated with an increased stroke incidence in cancer patients, and this association is
prominent and dose-dependent for prostate cancer patients. Further large population-based studies or large-scale randomized clinical trials to confirm these findings are required before any definite conclusions can be drawn. A possible underlying cellular mechanism for this association has yet to be identified.
REFERENCES
1. Portenoy RK. Treatment of cancer pain. Lancet. 2011; 377: 2236-47. 2. Goudas LC, Bloch R, Gialeli-Goudas M, et al. The epidemiology of cancer pain. Cancer investigation. 2005; 23: 182-90.
3. Ventafridda V, Tamburini M, Caraceni A, et al. A validation study of the WHO method for cancer pain relief. Cancer. 1987; 59: 850-6.
4. Gordon DB, Dahl JL, Miaskowski C, et al. American pain society
recommendations for improving the quality of acute and cancer pain management: American Pain Society Quality of Care Task Force. Archives of internal medicine. 2005; 165: 1574-80.
5. Quigley C. Opioids in people with cancer-related pain. Clinical evidence. 2008; 2008.
6. Koyyalagunta D, Bruera E, Solanki DR, et al. A systematic review of randomized trials on the effectiveness of opioids for cancer pain. Pain physician. 2012; 15: ES39-58.
7. Wiffen PJ, McQuay HJ. Oral morphine for cancer pain. Cochrane database of
systematic reviews. 2007; (4): CD003868.
8. Flemming K. The use of morphine to treat cancer-related pain: a synthesis of quantitative and qualitative research. Journal of pain and symptom management. 2010; 39: 139-54.
9. Siegel R, DeSantis C, Virgo K, et al. Cancer treatment and survivorship statistics, 2012. CA: a cancer journal for clinicians. 2012; 62: 220-41.
10. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain physician. 2008; 11: S105-20.
11. Borne J, Riascos R, Cuellar H, et al. Neuroimaging in drug and substance abuse part II: opioids and solvents. Topics in magnetic resonance imaging : TMRI. 2005; 16: 239-45.
12. Caplan LR, Hier DB, Banks G. Current concepts of cerebrovascular disease--stroke: stroke and drug abuse. Stroke; a journal of cerebral circulation. 1982; 13: 869-72.
13. Sloan MA, Kittner SJ, Rigamonti D, et al. Occurrence of stroke associated with use/abuse of drugs. Neurology. 1991; 41: 1358-64.
14. Jensen R, Olsen TS, Winther BB. Severe non-occlusive ischemic stroke in young heroin addicts. Acta neurologica Scandinavica. 1990; 81: 354-7.
15. Zhou Y, Fathali N, Lekic T, et al. Remote limb ischemic postconditioning protects against neonatal hypoxic-ischemic brain injury in rat pups by the opioid receptor/Akt pathway. Stroke; a journal of cerebral circulation. 2011; 42: 439-44. 16. Esse K, Fossati-Bellani M, Traylor A, et al. Epidemic of illicit drug use, mechanisms of action/addiction and stroke as a health hazard. Brain and behavior. 2011; 1: 44-54.
17. Hagan IG, Burney K. Radiology of recreational drug abuse. Radiographics : a
review publication of the Radiological Society of North America, Inc. 2007; 27:
919-40.
18. Andersen SN, Skullerud K. Hypoxic/ischaemic brain damage, especially pallidal lesions, in heroin addicts. Forensic science international. 1999; 102: 51-9. 19. Heidenreich A, Bellmunt J, Bolla M, et al. EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease. European
urology. 2011; 59: 61-71.
20. Mottet N, Bellmunt J, Bolla M, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer.
European urology. 2011; 59: 572-83.
21. Van Hemelrijck M, Garmo H, Holmberg L, et al. Absolute and relative risk of cardiovascular disease in men with prostate cancer: results from the Population-Based PCBaSe Sweden. Journal of clinical oncology : official journal of the American
Society of Clinical Oncology. 2010; 28: 3448-56.
22. Alibhai SM, Duong-Hua M, Sutradhar R, et al. Impact of androgen deprivation therapy on cardiovascular disease and diabetes. Journal of clinical
oncology : official journal of the American Society of Clinical Oncology. 2009; 27:
23. Azoulay L, Yin H, Benayoun S, et al. Androgen-deprivation therapy and the risk of stroke in patients with prostate cancer. European urology. 2011; 60: 1244-50. 24. Keating NL, O'Malley AJ, Freedland SJ, et al;. Diabetes and cardiovascular disease during androgen deprivation therapy: observational study of veterans with prostate cancer. Journal of the National Cancer Institute. 2010; 102: 39-46.
25. Robinson D, Garmo H, Lindahl B, et al. Ischemic heart disease and stroke before and during endocrine treatment for prostate cancer in PCBaSe Sweden.
International journal of cancer Journal international du cancer. 2012; 130: 478-87.
26. Chung SD, Chen YK, Wu FJ, et al. Hormone therapy for prostate cancer and the risk of stroke: a 5-year follow-up study. BJU international. 2012; 109: 1001-5.
Legends
Table 1. Demographics between stroke and non-stroke group
Table 2. Odds ratios for stroke between morphine and non-morphine group among cancer type
Table 3. Odds ratios for stroke type between morphine and non-morphine group Table 4. Odds ratios for stroke type between morphine and non-morphine group
