Abstract
Morphine, oxycodone, and fentanyl are commonly used to control cancer pain. Because these drugs have differences in receptor affinity or pharmacokinetic parameters, changing the opioid formulation may result in an unexpected outcome, depending on the patient’s condition. This study investigated whether low serum protein levels influence the effectiveness of opioid rotation by determining the impact of serum albumin levels on the analgesic effect before and after opioid rotation from morphine or oxycodone to fentanyl in cancer patients. The patients were classified into 3 groups according to their serum albumin levels before opioid rotation: group 1, <2.5 g/dL; group 2, from 2.5 g/dL to <3.0 g/dL; and group 3, ≥3.0 g/dL. There was no significant change in the percentage of patients with good pain control after rotation in group 1 or group 2; however, the percentage of patients with good pain control increased significantly in group 3. When the percentage of patients whose numerical rating scale scores increased, were unchanged, or decreased after rotation were compared, a significant difference in the percentage of those showing improvement was noted among the 3 groups and between groups 1 and 3. These findings suggest that monitoring serum albumin levels during fentanyl therapy is useful for pain management, and that the effectiveness of opioid rotation to fentanyl in patients with serum albumin levels of <2.5 g/dL should be carefully evaluated after rotation.
Opioids are widely used for the treatment of cancer pain. Switching to another opioid, i.e., opioid rotation, is recommended when it is necessary to improve pain control, reduce adverse reactions, change the administration route or take other measures during opioid therapy.1) Opioid rotation is routinely performed in clinical practice.2–4) Common opioids used to control cancer pain include morphine, oxycodone and fentanyl, all of which have different properties. Opioid receptors are broadly divided into 3 types, i.e., μ, κ and δ.5) Although all 3 drugs exert a potent analgesic effect via the µ-receptor, they show differences in affinity for different μ-receptor subtypes and other receptors,6–8) and these differences result in variations in adverse drug reactions.9,10) Assessment of pharmacokinetic parameters has revealed that the protein-binding rate of fentanyl is as high as 84.4%, whereas that of morphine is only 20–36% and that of oxycodone is 45%.11) When the association between the protein-binding rate of drugs and hypoalbuminaemia was investigated, it was observed that administration of a drug with a protein-binding rate of ≥85% (such as warfarin) to patients with hypoalbuminaemia led to an increase in the free form of the drug, causing an increase in its pharmacological action or adverse reactions.12) Kokubun and Yago13) reported that changes in protein binding should be considered during the clinical use of drugs with a protein-binding rate of ≥80%. They also stated that the efficacy of or adverse reactions to fentanyl administered as a continuous intravenous infusion or patch formulation may be increased when its protein-binding rate was decreased. It has been reported that providing appropriate nutrition increases the completion rate of chemotherapy or radiation therapy, helps to maintain a favourable clinical course and improves the quality of life of cancer patients.14,15) Nomura et al.16) studied the association between the serum albumin level and serum fentanyl concentration after transdermal administration of fentanyl. They classified 18 cancer patients into the following 2 groups according to their serum albumin levels: a normal albumin group (≥3.5 g/dL) and a low albumin group (<3.5 g/dL). Comparison of the 2 groups revealed lower serum fentanyl concentrations in the low albumin group than in the normal albumin group 9–24 h after transdermal administration of fentanyl. This result and the results of Kokubun and Yago, are completely conflicting. Therefore, we believe that it is interesting to examine the influence on the efficacy or adverse reactions, on administering fentanyl to patients with low albumin levels. In addition, patients with cancer often experience hypoproteinemia when undergoing standard medical treatment, and there are no reports addressing the association between analgesic effects and albumin levels. Considering this background, we considered that it is important to assess the influence of low serum protein levels on the analgesic effect of fentanyl in patients with cancer pain. Therefore, we classified patients into 3 groups according to the serum albumin levels of <2.5 g/dL, from 2.5 g/dL to <3.0 g/dL and ≥3.0 g/dL before opioid rotation. We then investigated whether serum albumin levels influence the analgesic effect of the 3 opioids before and after switching medications in cancer patients who underwent opioid rotation from morphine or oxycodone to fentanyl.
PATIENTS AND METHODS
SubjectsThe subjects included cancer patients who were admitted to Fujita Health University Hospital between 1 April 2010 and 30 September 2012 and who underwent opioid rotation to fentanyl during this period. Patients were excluded from the study if they met any of the following criteria during the observation period: initiation or change in chemotherapy, radiation therapy or analgesic therapy (including adjuvant analgesics); change in the analgesic dose (including adjuvant analgesics); a temperature of ≥38°C; an increase in C-reactive protein (CRP) levels or hepatic or renal dysfunction. In addition, patients were excluded if they had dermatosis that could affect the absorption of fentanyl from patches, a history of liver cirrhosis or heart failure or any other circumstance that made them ineligible for the study because of a possible influence on assessment of the endpoints.
InvestigationsThis retrospective study used information from the electronic medical records of Fujita Health University Hospital. To assess baseline patient characteristics, age, sex, primary cancer, reason for opioid rotation and dose of opioid were investigated. Blood biochemical parameters included the serum levels of total protein, albumin and creatinine; the levels of aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, sodium and potassium and the estimated glomerular filtration rate. Doses of opioids used before rotation were expressed as doses equivalent to oral morphine. Doses of oral oxycodone or infused morphine were converted to oral morphine-equivalent doses according to the National Comprehensive Cancer Network guidelines,4) i.e., infused morphine doses were converted to oral morphine-equivalent doses at a ratio of 1 : 3 and oral oxycodone doses were converted at a ratio of 1 : 2. Doses of transdermal fentanyl used after opioid rotation were expressed as the mean daily fentanyl release, whereas doses of infused fentanyl were expressed as the actual doses administered. In patients who received transdermal fentanyl, the equianalgesic ratio for opioid rotation was calculated as the oral morphine-equivalent dose divided by the mean daily fentanyl release, whereas the ratio was calculated as the oral morphine-equivalent dose divided by the actual dose of fentanyl administered in patients who received fentanyl infusion. The analgesic effect of each opioid was evaluated on the basis of the frequency of using rescue medication, hospital pain management records and the numerical rating scale (NRS) score.4) Adverse reactions to opioids were assessed on the basis of the need for medical treatment of the reaction, patient’s complaints noted in the medical records and laboratory data. This study was conducted according to a protocol approved by the Ethical Review Board of Fujita Health University Hospital for Epidemiological or Clinical Research and the Ethics Committee of Kinjo Gakuin University, with adequate ethical consideration given to the subjects.
AssessmentThe patients were classified into the following 3 groups according to their serum albumin levels before opioid rotation: group 1, serum albumin levels of <2.5 g/dL; group 2, serum albumin levels of from 2.5 g/dL to <3.0 g/dL and group 3, serum albumin levels of ≥3.0 g/dL. Assessment was performed during a 6-d period that spanned 3 d before opioid rotation and 3 d after rotation.
To assess pain control, the occurrence of moderate or severe pain on ≥2 of the 3 d was classified as poor pain control, and other outcomes were classified as good pain control (no description was recorded as unknown). Moderate or severe pain was defined according to any of the following criteria: documented complaints of pain ≥3 times daily, use of rescue medication for pain ≥3 times daily, moderate or severe pain according to the description in the medical record and an NRS score of ≥3. The effect of opioid rotation on pain control was evaluated by assessing the changes in the number of patients with good and poor pain control after rotation. If the NRS score was noted in the medical record, changes in this score after rotation were classified into 3 grades (decreased, unchanged or increased) and were compared in the same manner.
The presence or absence of adverse reactions was also determined. An adverse reaction was defined as any of the following: drug treatment was required for the reaction, the description in the medical record was consistent with an adverse reaction or a laboratory abnormality was detected that was at least twice the upper limit of the institutional reference range.
Statistical AnalysisVariables with a normal distribution were expressed as mean±standard deviation (S.D.), and other variables were expressed as median (interquartile range). To analyse the changes in the laboratory parameters after opioid rotation in individual patients, variables with a normal distribution were assessed by the paired t-test and other variables were assessed with the Wilcoxon signed rank test. To investigate the differences in the laboratory parameters among the 3 groups, ANOVA was used to assess variables with a normal distribution, whereas the Kruskal–Wallis test was used to assess other variables. The McNemar test was used to compare the incidence of adverse events and the analgesic effect after opioid rotation with those before rotation in individual patients. The chi-square test was used to compare the percentage of patients who experienced an adverse event as well as the percentage of patients with changes in the NRS score among the 3 groups. Statmate IV analytical software was used to perform all analyses, and p-value of <0.05 was considered to be statistically significant.
RESULTS
Baseline Patient CharacteristicsA total of 68 patients (44 men and 24 women) were included in this study. The average age of the patients was 68.3±9.4 years. Table 1 shows the sites of primary cancer in the subjects. Lung cancer was the most common tumour, followed by stomach cancer and pancreatic cancer. Table 2 lists the reasons for opioid rotation. The most common reason was adverse reactions, followed by changing the dosage form because of dysphagia associated with worsening of the patient’s condition. Assessment of the changes in hepatic and renal function in individual patients after opioid rotation revealed no significant difference (data not shown).
Table 1. Site of the Primary Tumor
| Tumor site | Number of patients |
|---|
| Lung | 13 |
| Stomach | 9 |
| Pancreas | 8 |
| Pharynx/Parotid gland | 7 |
| Lips/Tongue/Chin | 5 |
| Gallbladder/Bile duct | 4 |
| Rectum | 4 |
| Liver | 3 |
| Ureter/Bladder | 3 |
| Uterus/Ovary | 2 |
| Kidney | 2 |
| Breast | 2 |
| Bone marrow | 1 |
| Small intestine | 1 |
| Esophagus | 1 |
| Prostate | 1 |
| Skin | 1 |
| Unknown | 1 |
Data are for 68 patients.
Table 2. Reasons for Opioid Rotation
| Reason | Number of patients |
|---|
| Adverse effects of current opioid | 25 |
| Dysphagia | 17 |
| Poor pain control | 9 |
| For outpatient treatment | 5 |
| Abdominal distension/Anorexia | 4 |
| Adverse effects of anticancer therapy | 1 |
| Refusal of current therapy | 1 |
| Unknown | 6 |
Data are for 68 patients.
Table 3 summarizes the number and percentage of patients who experienced adverse events before or after opioid rotation. Each time a patient experienced an adverse event, it was counted; thus, a single patient could have been counted more than once in this table. The incidence of somnolence and constipation decreased significantly after opioid rotation. After rotation, hepatic dysfunction, cutaneous symptoms and respiratory depression developed in 1 patient each. Of the 68 patients, 52 experienced adverse events before rotation, whereas 34 experienced after rotation, and there was a significant decrease in the number of patients with adverse events after rotation (p=0.00091) (data not shown). Furthermore, we compared each group in terms of the percentage of patients who experienced adverse events before or after opioid rotation. The percentage of patients who experienced adverse events before opioid rotation did not differ among the 3 groups. In group 1, the percentage of patients decreased significantly (10 vs. 17 of 20 patients; p=0.039). In group 2, the percentage also decreased significantly (12 vs. 19 of 24 patients; p=0.039). However, no significant difference in the percentage of patients was found in group 3 (12 vs. 16 of 24 patients; p=0.34).
Table 3. Adverse Events before and after Opioid Rotation
| Before rotation | After rotation | p Value |
|---|
| Somnolence | 16 (23.5) | 9 (13.2) | 0.039 |
| Delirium | 9 (13.2) | 5 (7.4) | 0.13 |
| Nausea/Vomiting | 16 (23.5) | 11 (16.2) | 0.33 |
| Abdominal fullness | 1 (1.5) | 0 (0) | — |
| Constipation | 24 (35.3) | 7 (10.3) | 0.00024 |
| Hepatic dysfunction | 0 (0) | 1 (1.5) | — |
| Cutaneous symptoms | 0 (0) | 1 (1.5) | — |
| Respiratory depression | 0 (0) | 1 (1.5) | — |
Data are for 68 patients. Values are indicated as the number (percentage).
Table 4 presents the baseline characteristics and laboratory data for the 3 groups of patients classified according to their serum albumin levels. Patients for whom the efficacy of pain control was unknown were excluded from this assessment; accordingly, 65 of the 68 patients were included. Comparison of the 3 groups revealed a significant difference in serum total protein levels and serum albumin levels but did not reveal any significant difference in other laboratory parameters. In each group, the changes in the laboratory parameters before and after opioid rotation were assessed for individual patients; however no significant difference was noted (data not shown).
Table 4. Baseline Characteristics of the Groups According to Serum Albumin Levels
| Total (n=65) | Group 1 | Group 2 | Group 3 | p Value |
|---|
| Serum albumin |
|---|
| <2.5 g/dL (n=18) | ≥2.5–<3.0 g/dL (n=23) | ≥3.0 g/dL (n=24) |
|---|
| Sex (male, female) | 42, 23 | 11, 7 | 17, 6 | 14, 10 | 0.5 |
| Age (years) | 68.2±9.5 | 67.6±10.8 | 69.6±9.9 | 67.3±8.3 | 0.68 |
| Serum total protein (g/dL) | 6.1±0.8 | 5.4±0.9 | 6.0±0.5 | 6.5±0.6 | 0.00048 |
| Serum albumin (g/dL) | 2.9±0.7 | 2.0±0.3 | 2.7±0.1 | 3.5±0.4 | <0.0001 |
| Aspartate aminotransferase (U/L) | 25.5 (19.0–41.0) | 28.5 (18.8–47.3) | 24.5 (18.5–34.5) | 26.0 (19.8–48.8) | 0.45 |
| Alanine aminotransferase (U/L) | 21.0 (12.0–40.5) | 21.5 (13.5–41.8) | 17.0 (11.8–36.0) | 23.5 (13.5–38.0) | 0.68 |
| Blood urea nitrogen (mg/dL) | 17.2 (12.8–20.7) | 17.8 (15.2–27.3) | 18.5 (15.9–23.2) | 12.9 (10.5–17.2) | 0.75 |
| Serum creatinine (mg/dL) | 0.74 (0.59–0.98) | 0.75 (0.65–1.01) | 0.70 (0.57–1.12) | 0.74 (0.57–0.85) | 0.59 |
| Estimated glomerular filtration rate (mL/min/1.73 m2) | 75.1 (55.3–95.6) | 63.5 (54.8–88.2) | 78.8 (54.3–95.9) | 75.8 (61.0–102.3) | 0.49 |
Variables with a normal distribution are expressed as the mean±S.D., and other data are shown as the median (interquartile range).
Table 5 lists the opioids used before and after rotation, and Table 6 shows opioid doses and equianalgesic ratios for each group. As can be seen in Table 6, all doses were converted for opioid rotation by using the equianalgesic ratio specified in the package insert of each drug. There was no significant difference in opioid doses or equianalgesic ratios among the 3 groups before or after rotation.
Table 5. Opioids Used for Rotation
| Total (n=65) | Group 1 (n=18) | Group 2 (n=23) | Group 3 (n=24) |
|---|
| Oral oxycodone→Intravenous fentanyl | 4 | 1 | 2 | 1 |
| Oral oxycodone→Transdermal fentanyl | 49 | 12 | 17 | 20 |
| Intravenous morphine→Intravenous fentanyl | 5 | 3 | 2 | 0 |
| Intravenous morphine→Transdermal fentanyl | 6 | 2 | 1 | 3 |
| Oral morphine→Intravenous fentanyl | 1 | 0 | 1 | 0 |
Table 6. Opioid Dosages in the 3 Serum Albumin Groups
| Total (n=65) | Group 1 (n=18) | Group 2 (n=23) | Group 3 (n=24) | p Value |
|---|
| Before rotation |
| Oral morphine (mg/d) | 46.8±28.4 | 44.2±21.7 | 47.4±30.9 | 48.3±31.6 | 0.89 |
| After rotation |
| Fentanyl (mg/d) | 0.44±0.27 | 0.39±0.16 | 0.47±0.33 | 0.46±0.27 | 0.65 |
| Equianalgestic ratio (Oral morphine/Fentanyl) | 106.0±30.7 | 112.3±36.4 | 102.2±28.1 | 104.7±28.5 | 0.56 |
Figure 1 summarizes pain control before and after rotation in the 65 evaluable patients classified into the 3 serum albumin groups. There was no significant difference in the percentage of patients with good pain control among the groups before rotation. There was no significant change in the percentage of patients with good pain control after rotation in group 1 or group 2, whereas the percentage of patients with good pain control increased significantly in group 3. To assess the changes in pain control in more detail, changes in the NRS score after rotation were compared among the 3 serum albumin groups in the 63 patients whose NRS scores were available. (Two patients were excluded because the NRS score could not be determined correctly on account of impaired consciousness or inaudibility.) In the group with serum albumin levels of <2.5 g/dL, 26.3% of the patients showed increased scores, 26.3% showed no change and 47.4% showed decreased scores. In the group with serum albumin levels of from 2.5 g/dL to <3.0 g/dL, the numbers were 9.1%, 45.5% and 45.5%, respectively, whereas in the group with serum albumin levels of ≥3.0 g/dL, the numbers were 0%, 30.4% and 69.6%, respectively. There was a significant difference in the percentage of patients showing improvement among the 3 groups (p=0.041) and also in the percentage of patients showing improvement between groups 1 and 3 (Fig. 2).
DISCUSSION
The present study investigated whether serum albumin levels influence the analgesic effect of fentanyl for cancer pain in patients who underwent opioid rotation. Comparison of patients whose serum albumin levels were ≥3.0 g/dL with those whose levels were <2.5 g/dL with respect to pain control based on NRS scores showed that a higher percentage of patients responded to fentanyl in the former group. Nomura et al.16) administered transdermal fentanyl to patients with low or normal serum albumin levels and assessed the changes in serum fentanyl concentrations. They found no significant difference between the 2 groups up to 6 h after patch application. However, patients with low albumin levels had significantly lower serum fentanyl concentrations than those with normal albumin levels 9–24 h after application. Okazawa and Orii17) administered transdermal fentanyl to patients with low or normal serum albumin levels and assessed the analgesic effect. They reported that the percentage of patients with normal serum albumin levels who experienced good pain control was much higher than that of patients with low serum albumin levels. These reports focused on transdermal administration of fentanyl, but we excluded the factor that influenced the absorption process of transdermal fentanyl as much as possible and analysed patients with continuous intravenous infusion as well as patients with patch formulation. In addition, these were divided into 2 groups based on a borderline serum albumin level of 3.5 g/dL. Because it becomes often a hypoprotein state in patients with cancer who are under the medical treatment popularly, we divided patients into 3 groups based on the borderline serum albumin levels of 3.0 g/dL and 2.5 g/dL. We then determined the influence of low albumin levels on the analgesic effect. The present study revealed that serum albumin levels of <2.5 g/dL influenced the analgesic effect of fentanyl in patients who received transdermal or injectable formulations. This suggests that low albumin levels influence various factors that affect the pharmacokinetics of fentanyl, including its absorption. The possibility that the differences in the nutritional status influence the pharmacokinetics of fentanyl cannot be ruled out. However, the underlying mechanisms remain unknown at present, and this issue requires further investigation. Twycross et al.18) reported that opioid equianalgesic ratios are estimates based only on the standard doses of morphine. For example, the frequency of errors increases with the increase in the dose from a morphine-equivalent dose of 2 g/d. Tomibayashi et al.19) reported 2 patients receiving oxycodone (240 or 720 mg/d) who underwent opioid rotation to fentanyl and stated that the dose of fentanyl had to be increased stepwise to prevent adverse reactions such as respiratory depression and impaired consciousness. Our study was conducted in patients who were receiving opioids at an oral morphine-equivalent dose of 46.8±28.4 mg/d. When the protein-binding rate of fentanyl is taken into consideration, it is unclear whether similar results would be obtained in patients receiving higher opioid doses; this issue should be investigated in the future.
Opioid rotation is generally performed when there is a poor response to the current opioid therapy in order to reduce adverse reactions, change the administration route or for various other reasons.2–4) In our study, the most common reason for opioid rotation was the development of adverse reactions, followed by the need to change the dosage form because of dysphagia and then because of inadequate analgesia. We found that the incidence of adverse events was significantly lower after rotation to fentanyl than before rotation, indicating that one of the aims of opioid rotation (reducing adverse events) could be achieved. The finding that the incidence of somnolence and constipation decreased after rotation to fentanyl was consistent with findings from previous reports.9,20,21)
In our study, the exclusion criteria were established to minimize the influence of factors that may affect pain control, serum albumin levels or drug metabolism. These criteria included changing or initiation of chemotherapy, radiation therapy or analgesics (including adjuvant analgesics); changing analgesic doses (including adjuvant analgesics); an increase in CRP levels and hepatic or renal dysfunction during the observation period, as well as a history of liver cirrhosis or heart failure, because these factors could interfere with evaluation of the analgesic effect or adverse reactions. Other exclusion criteria were the presence of dermatosis and a temperature ≥38°C during the observation period, because these factors could influence the absorption of fentanyl from the patch.22,23) In particular, patients with dermatosis were excluded in consideration of the influence of such a disease on the absorption of fentanyl from patch preparations. It was previously reported that undernourished patients often have poor skin conditions and that the skinfold thickness influences the analgesic effect of fentanyl patches.17) In our study, the skin condition of the patients may have influenced the analgesic effect of fentanyl, although such an influence could not be assessed because the study was conducted retrospectively.
The results of the present study suggest that patients with serum albumin levels of <2.5 g/dL may not respond well to rotation to fentanyl. Twycross and Wilcock24) stated that cancer patients have total pain, which can be alleviated only by controlling physical pain. Therefore, if patients with low serum albumin levels do not achieve pain relief, nutritional management will be difficult, and a vicious circle may become established during treatment. Hohenberger and Wünscher25) presented pain relief and nutritional support as the 2 main objectives of palliative medicine. Nutritional management of cancer patients helps to reduce the damage to normal tissues, promotes regeneration/recovery of damaged normal tissues, corrects metabolic abnormalities associated with anticancer therapy, improves nutritional disorders associated with adverse drug reactions, increases immunocompetence by providing important nutrients and provides nutritional support for patients with terminal cancer.14) The results of our study suggest the possibility that the nutritional status can influence pain management with opioids.
In conclusion, it is useful to monitor serum albumin levels during fentanyl therapy. In particular, when patients with serum albumin levels less than 2.5 g/dL undergo opioid rotation from morphine or oxycodone with a different pharmacokinetic parameter to fentanyl, the effectiveness of pain control should be carefully evaluated after rotation. Extension of the present study should produce new findings regarding opioid therapy for cancer patients and contribute to pain management.
REFERENCES
- 1) World Health Organization. Cancer pain relief, 2nd edition. World Health Organization, Geneva (1996).
- 2) Donner B, Zenz M, Tryba M, Strumpf M. Direct conversion from oral morphine to transdermal fentanyl: a multicenter study in patients with cancer pain. Pain, 64, 527–534 (1996).
- 3) Mercadante S. Opioid rotation for cancer pain: rationale and clinical aspects. Cancer, 86, 1856–1866 (1999).
- 4) National Comprehensive Cancer Network (Version 2.2013). NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Adult Cancer Pain.
- 5) Martin WR, Eades CG, Thompson JA, Huppler RE, Gilbert PE. The effects of morphine- and nalorphine-like drugs in the nondependent and morphine-dependent chronic spinal dog. J. Pharmacol. Exp. Ther., 197, 517–532 (1976).
- 6) Chen JC, Smith ER, Cahill M, Cohen R, Fishman JB. The opioid receptor binding of dezocine, morphine, fentanyl, butorphanol and nalbuphine. Life Sci., 52, 389–396 (1993).
- 7) Monory K, Greiner E, Sartania N, Sallai L, Pouille Y, Schmidhammer H, Hanoune J, Borsodi A. Opioid binding profiles of new hydrazine, oxime, carbazone and semicarbazone derivatives of 14-alkoxymorphinans. Life Sci., 64, 2011–2020 (1999).
- 8) Nielsen CK, Ross FB, Lotfipour S, Saini KS, Edwards SR, Smith MT. Oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studies in two rat models of neuropathic pain. Pain, 132, 289–300 (2007).
- 9) Ahmedzai S, Brooks D, the TTS-Fentanyl Comparative Trial Group. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy, and quality of life. J. Pain Symptom Manage., 13, 254–261 (1997).
- 10) Yang YR, Lee EHY, Chiu TH. Electrophysiological and behavioral effects of Tyr-D-Arg-Phe-Sar on locus coeruleis neurons of the rat. Eur. J. Pharmacol., 351, 23–30 (1998).
- 11) Meuldermans WE, Hurkmans RM, Heykants JJ. Plasma protein binding and distribution of fentanyl, sufentanil, alfentanil and lofentanil in blood. Arch. Int. Pharmacodyn. Ther., 257, 4–19 (1982).
- 12) Ishizaki T. Clinical Pharmacology Lectures, Igaku Shoin Ltd., Japan, pp. 89–92 (1985).
- 13) Kokubun H, Yago K. Pharmacokinetics of opioids. Jpn. Hospice and Palliative Care, 14, 464–474 (2004).
- 14) Higashiguchi T. Cancer patient therapy and nutritional support. Gan To Kagaku Ryoho, 38, 1235–1240 (2011).
- 15) Rivadeneira DE, Evoy D, Fahey TJ 3rd, Lieberman MD, Daly JM. Nutritional support of the cancer patient. CA Cancer J. Clin., 48, 69–80 (1998).
- 16) Nomura M, Inoue K, Matsushita S, Takahari D, Kondoh C, Shitara K, Ura T, Hayashi K, Kojima H, Kamata M, Tatematsu M, Hosoda R, Sawada S, Oka H, Muro K. Serum concentration of fentanyl during conversion from intravenous to transdermal administration to patients with chronic cancer pain. Clin. J. Pain, 29, 487–491 (2013).
- 17) Okazawa M, Orii T. The clinical utility of serum albumin for pain control by fentanyl patch. Jpn. J. Pharm. Palliat. Care Sci., 1, 53–58 (2008).
- 18) Mortimer J, Charlesworth S, French S, Howard P, Toller CS. Palliative care formulary, 4th ed., (Twycross R, Wilcock A eds.) Palliativedrugs.com Ltd., United Kingdom, pp. 345–428 (2011).
- 19) Tomibayashi A, Nakayama H, Kagaya K, Yoneyama S, Suzuki N, Watanabe T, Sasaki S. Two cases using high dose of fentanyl patch for cancer pain. Jpn. J. Cancer Clin., 57, 135–140 (2011).
- 20) Ordóñez Gallego A, González Baŕon M, Espinosa Arranz E. Oxycodone: a pharmacological and clinical review. Clin. Transl. Oncol., 9, 298–307 (2007).
- 21) Heiskanen T, Kalso E. Controlled-release oxycodone and morphine in cancer related pain. Pain, 73, 37–45 (1997).
- 22) Ashburn MA, Ogden LL, Zhang J, Love G, Basta SV. The pharmacokinetics of transdermal fentanyl delivered with and without controlled heat. J. Pain, 4, 291–297 (2003).
- 23) Moore KT, Sathyan G, Richarz U, Natarajan J, Vandenbossche J. Randomized 5-treatment crossover study to assess the effects of external heat on serum fentanyl concentrations during treatment with transdermal fentanyl systems. J. Clin. Pharmacol., 52, 1174–1185 (2012).
- 24) Twycross R, Wilcock A. Symptom management in advanced cancer, 3rd ed., Radcliffe Medical Press Ltd., United Kingdom, pp. 17–68 (2001).
- 25) Hohenberger P, Wünscher V. Supportive measures in palliation: pain therapy and nutrition. Chirurg, 70, 1422–1433 (1999).
