Analysis of Factors Related to the Use of Opioid Analgesics in Regional Cancer Centers in Japan

Abstract

Purpose:

The use of opioid analgesics and nonopioid medicines for the treatment of various symptoms in regional cancer centers is considered to be an index of the effectiveness of the structural plan for palliative care in such institutions. The present study aimed to establish an accurate representation of the actual use of opioid analgesics for palliative care in regional cancer centers.

Methods:

In November 2007, a questionnaire regarding the use of medications for palliative care was conducted in 288 regional cancer centers in Japan. Valid responses were received from 264 institutions (response rate, 91.4%).

Results:

All regional cancer centers reported using both opioid analgesics and nonopioid medicines. However, regarding opioid analgesics, the use of each standard strength ranged from 7% to 100%. The total amount of opioid analgesics used was 1739.6 ± 1216.5 g (mean ± SD). Factors found to be significantly related to the total amount of opioid analgesics used in an institution were the number of opioid analgesic medicines in use (p = 0.008), the number of inpatients with cancer (p < 0.001), the number of deaths among patients with cancer (p < 0.001), and the number of beds (p < 0.001).

Discussion:

Increase in the amount of opioid analgesics might improve the quality of palliative care at regional cancer centers.

Introduction

Since the morphine sustained-release tablet was first marketed in Japan in 1989, the annual consumption of morphine in Japan has increased every year. As a result, the total amount consumed in 2001 (842 kg) was 6.1 times the amount consumed in 1989 (138 kg).¹ However, these amounts remain 1/10 to about 1/6 of the total amount consumed in the United States and European countries.²

In 1990, the Japanese government established institutional standards for palliative care units (PCU) and began to conduct evaluations of institutions according to these standards. In 2002, the government also initiated the establishment of palliative care teams (PCT). Moreover, based on the 2006 Basic Law on Cancer, the government is working to improve and maintain regional cancer centers (RCC) for the purpose of equalizing care for patients with cancer by establishing a plan for cancer control. “Having a structural plan which offers palliative medicine” is included in the requirements for cancer institutions according to the plan. By November 2007, the government had specified 288 institutions.

In the present study, we investigated the amount of opioid analgesics used for reducing symptoms in RCC because published literature from overseas has analyzed the consumption of opioid analgesics for cancer pain treatment, and all have made reference to the correlation between the level of use and the degree of patient satisfaction.^3–6 Therefore, this work aims to elucidate the actual use of opioid analgesics for palliative care in RCC.

Methods

Survey

In November 2007, a questionnaire regarding the use of medications for palliative care was conducted for 288 RCC in Japan. Questionnaire surveys were sent to institutions by postal mail.

Questionnaire

Items in the questionnaire developed for the present research included the number of sickbeds, the number of inpatients with cancer in 2006, the number of deaths among patients with cancer in 2006, the number of pharmacists, the number of opioid analgesics used, the number of essential medicines used for palliative care, the presence of a PCU, the working conditions in the PCT (a total of seven items), the pharmacist's duties (a total of six items), difficulty with medical duties (a total of three items), the use of opioid analgesics and nonopioid medicines (NOM) for the treatment of various symptoms according to the essential drug list of the International Association for Hospice and Palliative-Care Conference,⁷ and the amount of opioid analgesics administered from October 2006 to September 2007. In addition, for this study, the opioid analgesics morphine, fentanyl, and oxycodone were included.

Questionnaires about palliative care were completed anonymously by the pharmacist or management representative most closely involved with palliative care and were returned on a voluntary basis. All data were grouped for statistical analysis, and the identity and affiliation of each respondent could not be linked to the content of their completed questionnaire.

Statistical analysis

Descriptive statistics were used to analyze data regarding the background of the institution, the use of opioid analgesics and NOM, and the amount of opioid analgesics used by the institutions. The amounts of morphine and opioid analgesics used at each institution were calculated. Opioid analgesics administered at each institution were converted to oral morphine equivalents using the following conversion ratios: oral morphine:oral oxycodone:tansdermal fentanyl pasting = 300:200:3 and oral:suppository:intravenous = 6:4:3.^8,9 Fentanyl injection, which is used for various pain treatments, was not subjected to conversion. In order to analyze factors related to the amount of opioid analgesics used at each institution, univariate analysis was conducted on each variable. We created a phantom using variables with p < 0.2 according to the univariate analysis. Furthermore, variable selection was conducted using the variable decreasing method (p < 0.05), and significantly relevant factors were identified by multivariate analysis.

Results

Background of RCC

Table 1 shows the background of the RCC. Questionnaires were recovered from 91.7% (264/288) of the institutions.

Table 1.

Background of the Regional Cancer Centers (n = 264)

Object		Mean ± SD	Median, range	n, %
No. of beds		587.8 ± 214.6	564.4, 171–1308	—
No. of inpatients in 2006^a		2523.8 ± 1860.7	2077.5, 197–13401	—
No. of deaths among patients with cancer in 2006^a		221.0 ± 126.3	200.0, 14– 985	—
No. of pharmacists		21.4 ± 12.1	19, 2–75	—
No. of opioid analgesics used		28.2 ± 5.0	28, 17–45	—
No. of essential medicines used for palliative care		62.9 ± 5.5	64, 44–71	—
Palliative care unit	Yes	—	—	46, 17.4
Working conditions in palliative care team
Presence of medical fees^a	Yes	—	—	38, 14.4
Presence of full-time clinicians^a	Yes	—	—	47, 17.3
Presence of full-time nurses^a	Yes	—	—	54, 20.5
Presence of exclusive pharmacists^a	Yes	—	—	42, 15.3
No. of patients consulted in 2006		78.3 ± 154.6	35, 0–1400	—
Working hours per week for the exclusive pharmacist		4.5 ± 5.1	3, 0–40	—
Pharmacist's duties
Attend conferences^a	Yes	—	—	205, 77.7
Attend ward rounds^a	Yes	—	—	160, 60.6
Opioid dose check^a	Yes	—	—	216, 81.8
Concomitant-drug check^a	Yes	—	—	195, 73.9
Self-management of opioid analgesics^a	Yes	—	—	217, 82.2
Medication education^a	Yes	—	—	199, 75.4
Difficulty with medical duties
Reservation of sufficient time for the exclusive pharmacist	Yes	—	—	95, 36.0
Misunderstanding of the use of opioids by the patient or family	Yes	—	—	204, 77.3
Medical cooperation in the community	Yes	—	—	160, 60.6

Data include institutions that did not provide an answer.

Use of opioid analgesics

Table 2 shows the status of the use of opioid analgesics in the institutions. Regarding the use of opioid analgesics, the use of each standard strength ranged from 7% to 100%.

Table 2.

Use of Opioid Analgesics in Regional Cancer Centers

Medicine		Dosage form	n	%
Morphine		Tablet	215	81
		Tablet (sustained release)	259	98
		Capsule (sustained release)	197	75
		Granule (sustained release)	97	37
		Powder	222	84
		Solution	247	94
		Suppository	264	100
		Injection	264	100
Oxycodone		Tablet (sustained release)	264	100
		Powder	230	87
		Injection (combinations)^b	18	7
Fentanyl		Transdermal	264	100
		Injection	264	100
Codeine		Tablet	51	19
		Powder	238	90
Dihydrocodeine^a		Powder	18	7
Buprenorphine^a		Suppository	250	95
		Injection	242	92
Pentazocine^a		Tablet	211	80
		Injection	260	99
Others^a	Tramadol	Injection	14	5
	Butorphanol	Injection	81	31
	Eptazocine	Injection	8	3

Data include institutions that did not provide an answer.

Although the precise mechanism is unknown, the figure includes combinations with hydrocotarnine, which enhance the effect of oxycodone.

Use of NOM

Table 3 shows the status of the use of NOM. Regarding the use of NOM, the use of each medicine ranged from 14% to 100%.

Table 3.

Present Status of the Use of Essential Medicines for Palliative Care in Regional Cancer Centers

		n	%
Nonopioid analgesics	All (8 medicines)	125	47
Acetaminophen	Acetaminophen	264	100
NSAID	Ibuprofen^a	155	59
	Diclofenac	263	99
	Loxoprofen	264	100
	Diclofenac suppository	263	99
	Flurbiprofen axetil injection^a	250	95
NSAID (COX-2 selective)	Etodolac^a	222	84
	Meloxicam	245	92
Anticonvulsant	All (5 medicines)	180	68
	Gabapentin	197	75
	Carbamazepine	264	100
	Clonazepam	260	99
	Zonisamide	231	88
	Sodium valproate	264	100
Antidepressant	All (9 medicines)	42	15
Tricyclic	Amitriptyline	260	99
	Amoxapine^a	185	70
	Nortriptyline^a	79	29
Tetracyclic	Mianserin^a	229	87
SSRI	Paroxetine	260	99
	Sertraline^a	152	58
	Fluvoxamine^a	243	92
SNRI	Milnacipran	240	90
Others	Trazodone^a	178	67
Antipsychotic	All (12 medicines)	52	20
D2 antagonist	Haloperidol	261	98
	Haloperidol injection	264	100
	Chlorpromazine^a	239	91
	Chlorpromazine injection	234	89
	Prochlorperazine	259	98
	Prochlorperazine injection^a	141	53
	Levomepromazine	224	84
	Levompromazine^a injection	163	62
MARTA-SDA	Olanzapine^a	197	75
	Quetiapine	222	84
	Perospirone^a	158	59
	Risperidone	248	93
Insomnia treatment	All (8 medicines)	147	56
Short-acting	Zolpidem	260	99
	Brotizolam	254	96
	Rilmazefone	203	76
Intermediate-acting	Flunitrazepam	204	77
Sedative hypnotic	Flunitrazepam injection^a	205	78
	Midazolam injection^a	263	99
	Propofol injection	262	99
	Phenobarbital injection	263	99
Anti-anxiety	All (4 medicines)	208	79
	Etizolam	263	99
	Diazepam	264	100
	Ethyl loflazepate	247	94
	Lorazepam	216	82
Steroid	All (3 medicines)	261	98
	Dexamethasone	264	100
	Prednisolone	264	100
	Betamethasone	261	98
Anti-emetic	All (4 medicines)	248	93
	Domperidone	262	99
	Domperidone suppository	262	99
	Metoclopramide	259	98
	Metoclopramide injection	256	96
Antihistamines	All (4 medicines)	25	10
	Diphenhydramine^a	239	91
	Diphenhydramine^a (combinations)	177	67
	Diphenhydramine^a (combinations) injection	38	14
	Chlorpheniramine^a	211	79
Laxatives	All (7 medicines)	197	75
	Magnesium oxide^a	262	99
	Lactulose^a	259	98
	Sennoside^a	263	99
	Picosulfate^a	263	99
	Bisacodyl suppository^a	199	75
	Glycerin^a	263	99
Antidiarrheal	Loperamide^a	263	99
Anticholinergics	All (3 medicines)	133	50
	Scopolamine butybromide injection^a	259	98
	Scopolamine hydrobromide injection	133	50
	Atropine sulfate injection	263	99
Antihypercalcemic	All (2 medicines)	161	60
	Zoledronic acid injection^a	258	98
	Pamidronate injection^a	162	62
Others	All (3 medicines)	234	89
	Octreotide injection^a	256	96
	Ketamine injection^a	259	98
	Methylprednisolone	242	92

Data include institutions that did not provide an answer.

NSAID, nonsteroidal antinflammatory drug; COX-2, cycloxygenase-2; SSRI, selective seratonin reuptake inhibitor; SNRI, seratonin norepinephrine reuptake inhibitor; MARTA-SDA, multiacting receptor targeted antipsychotic-seratonin dopamine antagonist.

Analysis of factors related to the use of opioid analgesics

The mean morphine equivalent of opioid analgesics administered at the institutions was 1739.6 ± 1216.5 g.

Table 4 shows the factors found to be significantly related to the use of opioid analgesics according to univariate analysis (p < 0.1). Fourteen items in total were found to be significant factors. Table 5 shows the results using the phantom created using these 14 variables after performing variable selection using the variable decreasing method (p < 0.05), and significantly related factors were identified by multivariate analysis. As a result, the number of opioid analgesics used, the number of inpatients with cancer, the number of deaths among patients with cancer, and the number of sickbeds were found to be factors significantly related to the amount of opioid analgesics used.

Table 4.

Factors Related to the Annual Use of Opioid Analgesics (Univariate Analysis, n = 251)

Factor	r	p
No. of beds	0.40	<0.001
No. of inpatients in 2006	0.60	<0.001
No. of deaths among patients with cancer in 2006	0.63	<0.001
No. of pharmacists	0.46	<0.001
No. of opioid analgesics used	0.36	<0.001
No. of essential medicines used for palliative care	0.26	<0.001
Presence of palliative care unit	0.24	<0.001
Presence of medical fees	0.29	<0.001
Presence of full-time clinicians in palliative care team	0.22	0.002
Presence of full-time nurses in palliative care team	0.15	0.048
Presence of exclusive pharmacist in palliative care team	0.01	0.932
No. of patients consulted in 2006	0.26	<0.001
Working hours per week for the exclusive pharmacist	0.21	0.002
Attending conferences for palliative care team	0.05	0.403
Attending ward rounds with the palliative care team	0.06	0.322
Opioid dose check	0.05	0.461
Concomitant-drug check	0.02	0.770
Self-management of opioid analgesics	0.06	0.371
Medication education	0.12	0.060
Reservation of sufficient time for the exclusive pharmacist	0.04	0.531
Misunderstanding of the use of opioid analgesics by the patient or family	0.12	0.062
Medical cooperation in the community	0.06	0.373

Table 5.

Factors Related to the Annual Use of Opioid Analgesics (Multivariate Analysis, n = 251)

Factor ^a	t	p
No. of opioid analgesics used	2.67	0.008
No. of sickbeds	3.47	<0.001
No. of inpatients with cancer in 2006	5.14	<0.001
No. of deaths among in patients with cancer in 2006	6.52	<0.001

We created a phantom using variables with p < 0.2 according to the univariate analysis (Table 4) and significantly relevant factors were identified by multivariate analysis. Max-rescaled R-Square =0.717 (p < 0.001).

Discussion

In order to improve the care for patients with cancer in Japan, it is necessary to increase the amount of opioid analgesics used in Japan. This study is the first to investigate the use of opioid analgesics and NOM for treating various symptoms and the amount of various opioid analgesics used in RCC. The results can be summarized as follows: 1) although the opioid analgesics were used by all institutions, few institutions used all formulations; 2) the mean amount of morphine equivalent opioid analgesics used by each institution was 1739.6 ± 1216.5 g; 3) the factors found to be significantly related to the amount of opioid analgesics used at the institutions included four items from the multivariate analysis (p < 0.05).

Opioid analgesics were used by all institutions. However, among the 70 items included in the survey, the mean number of medicines used by the institutions was 28.2 ± 5.0, which suggests that few institutions use all formulations for each opioid analgesic. Institutions in Japan are resistant to adopting new medicines due to increasing expenses only increasing the number of opioid analgesics used when a generic drug becomes available and due to the complexity of managing multiple opioid analgesics.¹⁰ On the other hand, among the 72 medicines included in this survey, the mean number of medicines used was 62.9 ± 5.5, and little difference was observed between institutions.

The annual consumption of morphine in each country is considered to be an international index of cancer pain treatment.¹¹ In the annual report of the International Narcotics Control Board, Japan had the 49th highest opioid consumption in 2005–2007. It was several or more times less than the Western countries and several times more than the Eastern and Third World countries.¹² When the total amount of morphine equivalents was calculated for the 251 RCC that consume most of the morphine equivalents in Japan, the annual consumption was found to be approximately 450 kg. Therefore, the total amount of morphine equivalents used by RCC was identified as a measure by which we can evaluate the level of cancer pain treatment in Japan.

We examined the factors related to the amount of opioid analgesics used at each institution. After multivariate analysis, four items were found to be significantly related (p < 0.05). Previous studies in Japan have indicated that pharmacists participate in the planning by PCT, and opioid analgesic doses for patients increase with respect to the pain treatment.^13,14 Other previous research has shown that clinicians and pharmacists must cooperate in palliative care for patients, and that such care requires increased doses of opioid analgesics.¹⁵

In this analysis, the pharmacist's role in palliative care was not found to be a significantly related factor. Moreover, factors regarding the PCT were not found to be significant in the univariate analysis.

Although some limitations of the present study can be identified, we regard the present findings to be important because they are contradictory to previous work. First, the present study did not take into consideration the effect of the working conditions in the PCT, such as the acceptance rate of consultations, on the amount of opioid analgesics used. Moreover, the present study did not take into consideration the dispensing duties of the exclusive pharmacists at each institution. Therefore, the reservation of sufficient time for the exclusive pharmacist and the quality of palliative care related duties of the exclusive pharmacist differ greatly among institutions. Since there is a shortage of oncology pharmacists in Japan, the exclusive pharmacist is responsible for performing palliative care–related duties in almost all institutions. Moreover, the present study did not take into consideration the patient outcomes. Therefore, in future research it will be necessary to investigate patient outcomes using an analogous methodology. The number of opioid analgesics used that are not affected by such institutional factors as the number of sickbeds or the number of patients, which are included in the four factors identified in the multivariate analysis, are considered to be important options for increasing the amount of opioid analgesics used in these institutions. Therefore, the clinical implication of this study is that the participation of pharmacists in adopting new medicines at each institution is essential for simplifying the management of opioid analgesics and effectively reducing cancer pain in Japan.

Further research will facilitate improvements in the standardization of the content of palliative care in each institution, including the administration of opioid analgesics, and should focus on patient outcomes.

Footnotes

Acknowledgments

The authors thank Tatsuya Morita, M.D. (Department of Palliative and Supportive Care, Palliative Care Team and Seirei Hospice, Seirei Mikatagahara General Hospital) for his helpful discussions and critical review of this article.

Author Disclosure Statement

No competing financial interests exist.

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