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Japanese Journal of Clinical Oncology Advance Access originally published online on May 22, 2007
Japanese Journal of Clinical Oncology 2007 37(4):302-309; doi:10.1093/jjco/hym017
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© 2007 Foundation for Promotion of Cancer Research

Clinical Experience with Transdermal and Orally Administered Opioids in Palliative Care Patients—A Retrospective Study

Katri Elina Clemens1,2, and Eberhard Klaschik1,2

1 Department of Science and Research, Centre for Palliative Medicine, University of Bonn, Germany
2 Department of Anaesthesiology, Intensive Care, Palliative Medicine and Pain Therapy, Malteser Hospital Bonn/Rhein-Sieg, Germany

For reprints and all correspondence: Katri Elina Clemens, Department of Anaesthesiology, Intensive Care, Palliative Medicine and Pain Therapy, Malteser Hospital Bonn/Rhein-Sieg, Von-Hompesch-Str. 1, 53123 Bonn, Germany. E-mail: Katri-Elina.Clemens{at}malteser.de

Received September 20, 2006; accepted November 8, 2006


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 Conflict of interest statement
 References
 
Background: Transdermal fentanyl is a widely used opioid for the treatment of cancer pain. Simplicity of use and high patient compliance are the main advantages of this opioid. However, based on our clinical experience, transdermal fentanyl is often not efficacious in terminally ill palliative care patients. We thus retrospectively examined the pain management and need for opioid switching in cancer patients admitted to our palliative care unit.

Methods: Of 354 patients admitted to our palliative care unit from 2004 through 2005, 81 patients were pre-treated with transdermal fentanyl. Demographic and cancer-related data (diagnosis, symptoms, pain score on a numeric rating scale (NRS)), analgesic dose at admission and discharge were compared. Statistics: mean ± SD, ANOVA, Wilcoxon's test was used for inter-group comparisons, significance P < 0.05, adjusted for multiple testing. Pain scores are given in median (range).

Results: Mean transdermal fentanyl dose at admission was 81.0 ± 55.8 µg/h. In 79 patients transdermal fentanyl treatment was discontinued. In two patients, analgesic treatment according to WHO I provided sufficient pain relief. The other 77 patients were switched to other opioids: 33 patients to oral morphine and 44 to oral hydromorphone. In patients switched to morphine the dose at discharge (104.7 ± 89.0 mg) was lower than at admission (165.5 mg morphine equivalence). In patients switched to hydromorphone the dose of 277.8 ± 255.0 mg morphine equivalent was higher at discharge than at admission (218.2 ± 131.4 mg morphine equivalence – considering an equianalgesic conversion ratio morphine: hydromorphone = 7.5: 1). Pain scores decreased significantly after opioid rotation (NRS at rest/on exertion: 4 (0–10)/7 (2–10) versus 1 (0–3)/2 (0–5); P < 0.001).

Conclusions: In the patient group switched to morphine, sufficient pain relief was achieved by lower equianalgesic morphine doses, compared with the doses at admission. In the patient group switched to hydromorphone, higher equianalgesic morphine doses were needed at discharge, considering an equianalgesic conversion ratio of morphine: hydromorphone = 7.5: 1. Patients with far advanced cancer often suffer from sweating and cachexia, which may have negative effects on the absorption of transdermal fentanyl. Opioid switching to oral morphine or hydromorphone was well tolerated and proved to be an efficacious option for cancer pain treatment.

Key Words: opioid switching • opioid-related side effects • cancer pain • palliative care • equianalgesic dose


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 Conflict of interest statement
 References
 
Cancer is one of the gravest of chronic illnesses (1). More than two thirds of patients with metastatic cancer experience severe pain (2), which has an enormously negative impact on the quality of life. The great majority of these patients require strong opioid analgesics for appropriate pain control (3). Morphine has been shown to be an effective analgesic and is recommended as a first-line opioid in the WHO Cancer Pain Relief Guidelines (4). However, only level C evidence supports this recommendation, reflecting the paucity of good-quality clinical studies in cancer pain (5).

Hydromorphone is a semi-synthetic opioid which was first synthesised in Germany by Knoll in the 1920s and introduced into clinical medicine in 1926 (6). Since then its use has become more widespread and by 1990 the World Health Organization Expert Committee had recognised it as one of the alternatives to morphine (7). Hydromorphone differs structurally from morphine in terms of substitution of one oxygen molecule for the 6-hydroxyl group and the hydrogenation of the 7–8 double bond of the morphine molecule (8).

Fentanyl is a synthetic opioid with short-acting analgesic activity after intravenous or subcutaneous administration. Its low molecular weight, high potency and lipid solubility make fentanyl suitable for delivery via the transdermal therapeutic system. TTS fentanyl provides continuous opioid delivery from 12.5 to 100 µg for up to 72 h (9). Simplicity of use and high patient compliance are the main advantages of this opioid. The transdermal therapeutic system (TTS) with fentanyl was released in the USA in 1992 and in Germany in 1995.

However, the application of analgesics by the oral route is still one of the major recommendations of the World Health Organization in their cancer pain guidelines, first published in 1986 (10).

The primary objective of this retrospective analysis was to evaluate why transdermal fentanyl often seems to be not efficacious, particularly in terminally ill palliative care patients. We compared analgesic doses (morphine equivalent), as well as pain intensity scores on a numeric rating scale (0–10 NRS), at admission and discharge. In addition, we evaluated the documented side effects at admission and reasons for opioid switching.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 Conflict of interest statement
 References
 
Of 354 patients admitted to our palliative care unit from January 2004 to 1 November 2005, 81 patients were pre-treated with transdermal fentanyl. Demographic and cancer-related data, such as diagnosis, symptoms, Karnofsky performance status, pain score on NRS, analgesic dose at admission and discharge were documented and compared. The use of non-opioid analgesic drugs and other drugs for symptom control were documented and evaluated as well. The treatment with transdermal fentanyl was discontinued in patients with insufficient analgesia and/or severe side effects. An oral titration, starting with 50% of the morphine equivalent dose of the latest fentanyl treatment with immediate-release formula of morphine or hydromorphone every 4 h had been administered for 2–4 days. After achievement of stable level of pain intensity the treatment was changed to a sustained-release formula, administered every (8–)12 h; individual rescue medication was prescribed and provided. If required, rescue doses (1/6 of the calculated daily dose) for management of breakthrough pain were administered as immediate-release formula. If rescue doses were required more than three times, basic doses of sustained-release formula were increased. The total doses at admission and discharge, as reported in this paper, do not include rescue doses.

Demographic patient- and disease-related data, such as cancer diagnosis or previous illnesses, side effects at admission and at discharge were evaluated and documented by the physician in charge at our palliative care unit, including the laboratory values of creatinine and all other clinically relevant laboratory parameters. Patients with serum creatinine values greater than 1.10 mg/dl, urea nitrogen values greater than 50 mg/dl and/or with intensity of pain on a numeric rating scale greater than 7 were switched to hydromorphone.

Assessments
The intensity of pain was measured on a numeric rating scale (0 = no pain, 10 = worst possible pain) at admission and at discharge. The Karnofsky performance scale index (0–100%) was used to classify patients functional impairment. Cachexia, the occurrence of adverse effects of medication, such as constipation, sweating, nausea, vomiting and other symptoms, i.e. dyspnoea, were categorised as either absent or existing. Pain intensity, side effects and other symptoms were assessed and documented on a daily basis. Renal impairment was defined as serum creatinine concentration > 1.10 mg/dl and/or blood urea nitrogen > 50 mg/dl.

Statistical Methods
Descriptive summaries are provided for patient demographics, cancer-related data, pain and side effects. Statistics: mean ± SD, ANOVA, Wilcoxon's test was used for inter-group comparisons, significance P < 0.05, adjusted for multiple testing. The pain scores are given in median (range). All analyses were done using SPSS version 11.5 for Windows 2000.


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 Conflict of interest statement
 References
 
Of the 354 patients from 2004 to 1 November 2005, 81 (22.8%) patients (age 65.4 ± 12.2 years (range 31–96); 49.4% men) were pre-treated with transdermal fentanyl on admission. In all patients, the reason for admission was inadequate control of pain and/or other symptoms. Mean Karnofsky index of all patients was 51.4 ± 14.1 (range 20–80), in patients switched to hydromorphon 55.5 ± 14.5 (range 30–80) and in patients switched to morphine 45.2 ± 12.0 (range 20–70). Mean transdermal fentanyl dose was 81.0 ± 55.8 µg/h (193.7 ± 134.0 mg morphine equivalent per day) in all patients. Mean transdermal fentanyl dose in patients switched to hydromorphone was 91.0 ± 55.0 µg/h and in those switched to morphine 69.0 ± 56.3 µg/h. Clinical and demographic patient information at baseline are summarised in Tables 1 and 2. The average length of stay was 12.8 ± 6.4 (range 5–35) days. The average survival time in patients treated with hydromorphone was 65.3 ± 106.1 (6–532) days and 60.0 ± 113.8 (5–427) days in patients treated with morphine (Table 2).


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  		Table 1. Patient and cancer-related data (n = 77)

 

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  		Table 2. Baseline data of patients (n = 77) and opioid doses at admission and at discharge (mean ± SD, (range))

 
The mean duration of transdermal fentanyl pre-treatment was 163.9 ± 300.5 days (10–1460 days) in all patients. In patients switched to morphine mean duration of transdermal fentanyl pre-treatment was 131.7 ± 124.0 days (10–365 days) and in patients switched to hydromorphone 201.4 ± 352.0 days (14–1460) (Table 2). Main symptoms at admission (n = 81) were insufficient analgesia in 77 (95.1%), sweating in 49 (60.5%), cachexia in 27 (33.3%), nausea in 39 (48.2%), vomiting in 22 (27.2%), constipation in 53 (65.4%) and dyspnoea in 23 (28.4%) patients. Symptoms at discharge were in 63 patients documented. Pain in five (6.2%), sweating in three (3.7%), cachexia in 27 (33.3%), nausea in six (7.4%), vomiting in three (3.7%), constipation in four (4.9%) and dyspnoea in seven (8.6%) patients (Fig. 1). Renal impairment was documented in 30 of 81 (37%) patients; nine (27%) patients of which were in the morphine group, 19 (43.2%) patients in the hydromorphone group (Table 2) and two patients who were treated with WHO I analgesics. Serum creatinine in all patients was 1.3 ± 1.2 mg/dl (range 0.26–7.92 mg/dl). However, serum creatinine concentration was significantly higher in patients switched to hydromorphone 1.5 ± 1.5 mg/dl (range 0.26–7.92 mg/dl) than in patients switched to morphine 0.8 ± 0.5 mg/dl (range 0.26–2.81 mg/dl) (P = 0.006) (Table 2 and Fig. 3). Blood urea nitrogen values in patients switched to hydromorphone was 64.0 ± 53.3 (14–217) mg/dl and in patients switched to morphine 54.0 ± 18.4 (35–93) mg/dl (P = 0.444). Thirty (91%) of patients switched to morphine had somatic, one (3%) neuropathic and two (6%) somatic and neuropathic pain. Of the patients switched to hydromorphone 38 (86%) had somatic, six (14%) somatic and neuropathic pain but none had only neuropathic pain.


Figure 1
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  		Figure 1. Main symptoms of patients at admission and at discharge (in %). All patients were pre-treated at admission with fentanyl. The treatment at discharge in all patients was morphine or hydromorphone.

 

Figure 3
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  		Figure 3. Comparison of morphine equivalent doses in patients switched to hydromorphone and morphine at admission and at discharge as well as serum creatinine concentration. Eighty-one patients were pre-treated with fentanyl at admission. Of these patients 44 were switched to hydromorphone and 33 to morphine.

 
In 79 patients the treatment with transdermal fentanyl was discontinued. In two patients analgesic treatment according to WHO I (dipyrone) provided sufficient pain relief. The other 77 patients were switched to other opioids: 33 patients to oral sustained-release morphine and 44 to oral sustained-release hydromorphone. In patients switched to oral morphine the dose at discharge (104.7 ± 89.0 mg morphine) was lower (P = 0.08) than at admission (165.5 mg morphine equivalent). In patients switched to oral hydromorphone the dose of 37.0 ± 34.1 mg hydromorphone (277.8 ± 255.0 mg morphine equivalent) was higher than at admission (218.2 ± 131.4 mg morphine equivalent – considering an equianalgesic ratio of morphine: hydromorphone = 7.5: 1) (P < 0.001) (Table 2 and Fig. 4). Co-analgesics at discharge were dipyrone in 56 (73.0%) patients, ibuprofen in 16 (21.0%), gabapentin in six (7.8%) and flupirtine in one (1.3%). Co-analgesics at admission were documented in 57 patients: dipyrone in 45 (58.4%), ibuprofen in 10 (13.0%) and amitriptyline in one (1.3%). Thirty-two (41.6%) patients were pre-treated with laxatives and 20 (62.5%) of these on a regular basis. There was missing data for 20 (26.0%) patients.


Figure 4
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  		Figure 4. Morphine and morphine equivalent doses at admission and at discharge. For hydromorphone group considering an equianalgesic conversion ratio morphine: hydromorphone = 7.5:1 as well as 5:1.

 
The frequency of request for rescue medication during the treatment with fentanyl was 5.9 ± 1.8 (3–13)/24 h (n = 32) versus 1.3 ± 0.8 (0–3)/24 h (P < 0.001) at discharge with morphine or hydromorphone.

Pain scores (Fig. 2) at admission decreased in all patients significantly after opioid switching to oral morphine or hydromorphone as follows: NRS at rest/on exertion (median): 4 (0–10)/7 (2–10) versus 1 (0–3)/2 (0–5); (P < 0.001). In patients suffering from somatic and neuropathic pain (n = 8) or only neuropathic pain (n = 1), pain scores decreased after opioid switching as follows: NRS at rest/on exertion: 5 (1–7)/8 (4–9) versus 2 (1–3)/3 (2–5). There was no difference in pain scores between morphine and hydromorphone group at admission.


Figure 2
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  		Figure 2. Pain scores on a numeric rating scale (NRS: 0 = no pain, 10 = worst possible pain) compared at admission and at discharge (median) by patients with somatic pain (n = 68) and somatic pain with neuropathic pain components (n = 9).

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 Conflict of interest statement
 References
 
Previous studies provided evidence that transdermal fentanyl is an effective opioid for the management of cancer pain and chronic non-cancer pain (3,11–14). In this retrospective analysis of our 2004 and 2005 data, we reviewed the reasons for switching opioid from transdermal fentanyl to oral morphine or hydromorphone. It has been noted that as many as 80% of cancer patients require one switch in their analgesic regimen and as many as 44% require trials of two or more systemically administered opioids (15). In all patients, the switching procedure was performed for clinical reasons such as insufficient analgesia, i.e. when an increase of fentanyl doses in the pre-clinical period had had no positive effect on the intensity of pain, and side effects that limited the use of fentanyl (13,14,16). Moreover, bearing in mind the poor health status of our patients, we considered that further increases of fentanyl doses would result in higher risks with regard to occurrence and intensity of side effects and toxicity, but most likely not serve to achieve sufficient pain control (17,18). Finally, other factors were taken into account, such as the difficulty to administer high doses because of the extended area of application and costs of medication. The results from this retrospective investigation demonstrate that in all patients sufficient control of their somatic pain was achieved soon after switching to orally administered morphine or hydromorphone. However, it should be noted that the very low percentage of neuropathic pain is probably the reason for these particularly good results in pain control with oral administered opioids. Neuropathic pain can be difficult to treat and short-term studies provide only equivocal evidence regarding the efficacy of opioids in reducing the intensity of neuropathic pain (19). The poor effect and analgesic efficacy of opioids in neuropathic pain reflects a reduction on their potency. Reduction of morphine antinociceptive potency is postulated to be due to the fact that nerve injury altered the activity of opioid systems or opioid specific signalling (20). These results are consistent with those reported in other studies (19,21,22) in which opioid switching from transdermal fentanyl or morphine to orally administered methadone provided effective pain control in 70–90% of patients with far advanced cancer. It has been claimed that opioid switching is an effective therapeutic means for a reduction of opioid-induced side effects in most patients (14,23,24).

One weakness of this analysis was that co-analgesics with which patients were pre-treated at admission were not documented in all patients and therefore comparison with co-analgesics at discharge was not possible.

The frequent occurrence of most opioid-induced side effects in our case series may have been related to the following factors: First, most of our patients had been pre-treated with high doses of transdermal fentanyl (median dose 81.0 ± 55.8 µg/h) and second, the patients were considerably debilitated (mean Karnofsky performance status 51.4 ± 14.1) and therefore must be seen as a patient group that is considered particularly sensitive to the side effects of opioids. Patients with Karnofsky performance scale index < 50% were classified as to their functional impairment as follows: unable to care for oneself; requires equivalent of institutional or hospital care; disease may be progressing rapidly (9). The mean length of survival in our patients was 55.9 ± 102.6 (2–532) days. There are only a few reports available about the use of transdermal fentanyl and occurrence of fentanyl-related side effects in terminal or dying cancer patients (25–27). Many reports, however, show a significantly lower incidence of constipation using transdermal fentanyl (12,28–30), but higher incidence of nausea and emesis (28). The very low percentage of constipation as well as of nausea and emesis in our patients at discharge is probably due to strict and continuous laxative treatment along with the oral opioid therapy as well as antiemetic treatment at least for 5–10 days after opioid switching. All patients pre-treated with transdermal fentanyl and without laxative therapy suffered from constipation at admission.

Renal impairment was present in 30 (37%) patients at the time of admission. However, creatinine and blood urea nitrogen may not reflect renal function adequately in cachectic, anorectic patients and therefore renal impairment may have been underdiagnosed. Finally, it is possible that our data may reflect an uncritical use of transdermal fentanyl as a high potent opioid for the treatment of patients with far advanced cancer in the catchment area of our palliative care unit (26).

Usually, switching from the opioid agonist fentanyl to other opioid agonists like morphine and hydromorphone is simple. However converting patients from one opioid to another requires careful consideration, particularly if patients are opioid-naïve or receiving high opioid doses. The oral titration should begin with 50% of morphine equivalent dose. A quick way of switching is to simply replace the previously administered opioid by morphine or hydromorphone and a careful titration until the lowest possible pain intensity is kept on a stable level. Afterwards, the immediate-release formula of the opioid used (morphine or hydromorphone) is changed for its sustained-release formula, to be administered every (8–)12 h. Because of the pharmacokinetics of transdermal fentanyl a prolonged titration phase of the opioid used for switching may be required. Fentanyl serum concentrations show inter-individual variability and its terminal half-life when administered transdermally at doses of up to 100 µg/h is approximately 13–25 h (31). To the best of our knowledge, no data exist regarding pharmacokinetic parameters when higher doses are used. Moreover, elderly, cachectic or debilated patients may have altered pharmacokinetics due to poor fat stores, muscle wasting or altered clearance (32). When transdermal patches are removed, fentanyl still is concentrated in the cutaneous layers and continues to be absorbed into the systemic circulation. The action of fentanyl continues for 12–24 h (17). Therefore, the initial administration of the purely arithmetically correct equianalgesic dose of another potent opioid, such as morphine or hydromorphone, without considering the clinical situation of the patient, could easily result in opioid overdosing.

Compared with the morphine equivalent dose at admission, at discharge sufficient pain relief was achieved with lower equianalgesic morphine doses but higher equianalgesic hydromorphone doses, based on a conversion ratio of 7.5: 1 (morphine: hydromorphone). Considering a conversion ratio of 5: 1, in patients switched to hydromorphone, the dose of 187.0 ± 169.3 mg morphine equivalent (37.0 ± 34.1 mg hydromorphone) has only little changed, compared to the dose at admission (218.2 ± 131.4 mg morphine equivalent; P = 0.1) (see Figs 3 and 4). For these results no clear explanation could be found. Therefore, it must be emphasised that equianalgesic tables should be used only as a very general guideline. In the literature, researchers recommend conversion ratios from 3.7 to 7.5 (33,34). The equianalgesic dose ratio is defined as the ratio of doses of two opioids required to produce the same analgesic effect (35,36). The half-life of drugs, their bioavailability, drug interactions, hepatic and renal clearance, and the patient's prior narcotic exposure, as well as his type of pain, however, must also be included in the factors for arithmetical equation when clinicians decide upon the initial dose for titration and/or the conversion ratio for switching. An understanding of the sources of variation in pharmacodynamic factors and pain mechanisms will lead to improved clinical dosing guidelines.

The objective of this analysis, however, was not to find the ultimate conversion ratio between transdermal fentanyl and oral morphine/hydromorphone but to detect probable reasons for poor pain control and the occurrence of opioid-induced side effects that are encountered in palliative clinical practice. We are well aware of the limited evidential power of retrospective analyses. However, most of our knowledge regarding the conduction of opioid switching, a procedure that is needed increasingly in patients with cancer pain, has been obtained from retrospective studies, case reports and a small number of prospective studies (17,33,37,38). There is an urgent need for prospective controlled studies that investigate possible improvements of conversion strategies and/or equianalgesic dose ratios. The conduction of randomised controlled trials of opioid switching and opioid use in patients with far advanced cancer, particularly patients in the terminal phase of their disease, however, is very difficult because of international and national ethical concerns with regard to clinical studies in extremely vulnerable patient groups.

Patients with far advanced cancer often suffer from sweating and cachexia as well as from reduced dermal blood circulation, which may have a negative effect on the absorption of transdermal fentanyl. Another disadvantage may be the relative inflexibility of transdermal systems with regard to dose adjustment, particularly in the treatment of patients with unstable pain. This may be shown by the frequency of request for rescue medication in our study, which was significantly higher during the treatment with fentanyl than at discharge under treatment with morphine or hydromorphone. Many patients require a change from one opioid to another because of the development of side effects or inadequate analgesia (13,39,40).

At our palliative care unit, opioid switching to oral morphine or hydromorphone has been well tolerated, safe and proved to be an efficacious and simple option for cancer pain treatment in patients with far advanced cancer. The reasons why the opioid dose at discharge in the hydromorphone group was higher than in the morphine group need to be investigated, specifically, if the conversion ratio used in clinical practice should be reconsidered or not. Another suggestion for further research is that the dose differences are probably related to the difference of metabolism of these opioids. In contrast to morphine, hydromorphone is not metabolised via cytochrome P450 and its isoenzyme 3A4 but via glucuronidation to hydromorphone-3-glucuronide (H3G). Therefore, there is a lower risk of interaction of hydromorphone with other substances (41,42).

Furthermore, genomic variations in drug-metabolising enzymes have been associated with side effects, incompatibility and variation in therapeutic efficacy of drugs (43). Pharmacogenetical research is needed to elucidate whether or not it is the case for hydromorphone. However, many different aspects need to be considered in the treatment of pain in advanced cancer patients, including the individual variability of pharmacokinetics of opioids.


   CONCLUSIONS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
Conflict of interest statement
 References
 
In the patient group switched from transdermal fentanyl to oral morphine, sufficient pain relief was achieved by lower equianalgesic morphine doses, compared with the doses at admission; in the patient group switched to oral hydromorphone, at discharge higher equianalgesic morphine doses were needed, considering an equianalgesic conversion ratio of morphine: hydromorphone = 7.5:1. Patients with far advanced cancer often suffer from sweating and cachexia as well as from reduced dermal blood circulation, which may have a negative effect on the absorption of transdermal fentanyl. Opioid switching to oral morphine or hydromorphone was well tolerated and proved to be an efficacious option for cancer pain treatment in patients with far advanced cancer.


   Conflict of interest statement
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 Conflict of interest statement
References
 
None declared.


   Acknowledgments
 
The authors acknowledge R. Sackler Research Foundation.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 Conflict of interest statement
 References
 
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