【招待講演 1】】15:40-16:40
座長 並木昭義（札幌医科大学）
オピオイドローテーションの臨床的意義
樽見葉子
Physician Consultant, Regional Palliative
Care Program, Grey Nuns Community Hospital
Clinical implication of opioid rotation
Yoko Tarumi, Regional Palliative Care Program, Grey Nuns Community Hospital【招待講演２】

9:20-10:20

座長

172-177

花岡一雄（東京大学）

Expectations of Peripheral Opioid Analgesia
J.G. Collins
Department of Anesthesiology, Yale University School of Medicine【ランチョンセミナー２】 11:40-13:00 座長 土肥修司（岐阜大学）
ランチョンセミナー／昼食
在宅ホスピス・緩和ケアにおける疼痛緩和の実際と問題点
在宅ホスピス・緩和ケアにおける疼痛緩和の実際と問題点
川越 厚（グループ・バリアン代表、ホームケアクリニック川越院長）
Management of cancer pain in outpatients
Atsushi Kawagoe
Home Care Clinic Kawagoe

179-180178

Clinical Implication of Opioid Rotation
Author: Yoko Tarumi, M.D., Regional Palliative Care Program, Edmonton, Alberta

A. Introduction
Pain relief and palliative care have been the focus of increasing attention both in Japan andinternationally. In Japan, cancer has been the leading cause of death since 1981. Three hundred
thousand of people died from cancer in 2000 (1). Although the consumption of morphine has beensignificantly increasing in Japan, the average daily consumption of opioid is still considerably lower
than in North America, Australia, Great Britain and western European countries (2). A 1996
survey (3) reflected generally poorer cancer pain control in Japanese university hospitals and cancer
centers compared to previous studies of the WHO analgesic ladder.
One factor that may be contributing to poorer pain control is the limited selection of opioids forcancer pain relief compared with many other developed nations. Morphine, codeine and fentanyl
transdermal therapeutic system are currently the only available opioid agonists for the managementof moderate to severe cancer pain in Japan. In contrast, hydromorphone, oxycodone andmethadone are available in addition to these three opioids in North America. Social and regulatory
barriers may pose significant obstacles to access, even for clinicians experienced with the use of
these agents.
B. What is Opioid Rotation?
Opioid rotation (also known as opioid substitution) is the practice of switching from one
opioid to another, in order to improve an unfavourable balance of analgesia and side effects.
Opioids are generally the most effective treatment for patients with cancer pain (4), and pain can beeffectively controlled in most cancer patients with minimal toxicity until their last time. Morphineappears to have no clinically relevant ceiling effect to analgesia. Clinical reports of morphine
dosed at 35-40 g/day emphasize this fact (5)(6). A point may be reached at which higher doses
could theoretically produce greater analgesia but dose escalation is not possible because adverse
effects supervene, thus effectively defining the responsiveness of the pain syndrome in thatparticular patient (5). Adverse effects of opioids are generally classified into two groups: (A) thoseusually seen with lower doses or in the early phase of opioid therapy, such as ventilatory depression,
nausea and constipation; (B) those that may occur with chronic opioid therapy and are thought to be
manifestations of central nervous systems hyperexcitability, such as allodynia, hyperalgesia,
myoclonus, hallucinations, and delirium (i.e. opioid neurotoxicity). Patients with predictors for
intractable pain such as neuropathic pain, incident pain, history of alcoholism or drug abuse,
expression of psychosocial distress as somatic symptoms, and rapid development of tolerance, may
experience opioid dose escalation and be at higher risk of opioid neurotoxicity (7).
The rationale for opioid rotation is based on inter-individual variability in response todifferent opioids, or intra-individual variability in response to the same opioid over time, which arecommonly appreciated clinical phenomena in the management of cancer pain. There have beenvarious hypotheses to explain these observations:
B-1-1. Genetic factors Genetic factors may be important in determining patterns of opioid172sensitivity. For example, some mouse strains are deficient in their expression of mu receptors (8),and are correspondingly insensitive to the analgesic effects of morphine (9). Sensitivity to mu andkappa analgesia has been demonstrated to vary independently across mouse strains, suggesting thateach receptor subtype is under independent genetic control (10). It may be postulated, therefore,that analgesic and non-analgesic response to an opioid in humans may depend on a geneticallydetermined pattern of expression of receptor subtypes for which that opioid is selective.
B-1-2. Opioid tolerance and incomplete cross-tolerance Individual variability in response toopioids has been postulated to reflect the development of tolerance and the existence of incomplete
cross-tolerance between opioids (11). Analgesic tolerance is a phenomenon in which exposure to
the opioid itself causes the patient who has achieved analgesia to require a higher dosage tomaintain the same level of effect (12). Tolerance may also develop to adverse effects of opioids.
Various mechanisms are thought to underlie incomplete cross-tolerance between opioids. In vivo
studies comparing mu and kappa agonists suggest that the limited cross-tolerance results in partfrom the presence of multiple opioid receptor subtypes (13). Incomplete cross-tolerance among
mu-opioid agonists may result from differences in the intrinsic efficacy (14). If tolerance for
analgesia develops more rapidly than for adverse effects from opioids, this could manifest clinicallyas an imbalance in analgesic and adverse effects. Switching opioids could restore a favourable
balance if cross-tolerance was incomplete, and if cross-tolerance for analgesia was less than that foradverse effects.
B-1-3. Opioid metabolites Morphine undergoes glucuronide conjugation and become two major
metabolites: morphine-3-glucuronide (M-3-G) and morphine-6-glucuronide (M-6-G) (15). In
animal models, M6G is 10- to more than 100-fold more potent an antinociceptive agent thanmorphine, and is longer acting when given in equi-effective doses (16).
M-3-G has no intrinsic analgesic action, consistent with its poor affinity for classicalinhibitory opioid receptors in vitro (17). Following intracerebroventricular (ICV) and intrathecal
administration, M-3-G evokes dose-dependent excitatory behavioral effects in rodents, and has a
10-fold higher excitatory potency than morphine (18)(19). ICV M-3-G can attenuate morphine- or
M-6-G-induced antinociception and ventilatory depression (20). Although the effects of M-3-G inhumans have not been well documented, patients who developed myoclonus, confusion or seizures
on morphine in the setting of renal failure were found to have high plasma and cerebrospinal fluid(CSF) levels of M-3-G (21)(22).
Clinically, the plasma and CSF concentrations of M-3-G exceed those of morphine by
several-fold after single doses of morphine (23), and by as much as 10- to 20-fold in patients
receiving morphine chronically (24). A systematic review showed that metabolite ratios of M-6-G
and M-3-G to morphine were higher in renal impairment, and routes of administration which
avoided first pass metabolism (intravenous, transdermal, rectal, intramuscular, epidural andintrathecal) resulted in lower metabolite production than oral, sublingual, or buccal (25). Opioid
rotation may possibly benefit patients with opioid hyperexcitability by allowing clearance of theoffending metabolites. Theoretically, opioids without known active metabolites, such as methadone,
may be associated with a lower incidence of opioid-induced hyperexcitablity (26).
Numerous case reports and small retrospective case series have suggested improvement in
the balance of opioid analgesia and adverse effects in cancer patients after opioid rotation. Threelarge retrospective studies have supported these observations (27)(28)(29).
Three small
prospective uncontrolled studies (30)(31)(32) have also yielded positive findings.

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B-2. Other indications for opioid rotation
Other issues of a clinical, practical or economic nature may influence a decision to switch opioids.
Fentanyl transdermal therapeutic system is a favourable option for patients who have stable pain but
difficulty with oral intake due to disorders of the gastrointestinal tract or dysphagia secondary toneurological disease. However, due to the prolonged time to achieve steady-state blood levels 33),
this delivery system is not suitable for situations in which rapid dose titration is required (e.g. acute
uncontrolled pain or incident pain without an appropriate breakthrough analgesic regimen).
Methadone’s unique properties include lack of known active metabolites (34), possible antagonismof the N-methyl-D-aspartate receptor (35), incomplete cross-tolerance with other opioids (36) and alogarithmic increase in relative potency at higher doses (37). It is also the least expensive opioid.
Methadone may therefore be advantageous in the settings of renal failure, neuropathic pain, opioid
tolerance and requirement for high opioid doses. Cost-effectiveness may be a crucial issue forJapanese palliative care units, for which the cost of care is already fixed, as well as for the Japanese
medical system in general, which is carrying a huge debt.

C. Clinical Implications
When confronted with a patient with an unsatisfactory response to opioid therapy, acareful multidimensional assessment of the underlying pain is essential. A multidimensional
assessment takes into account not only characteristics of the pain and opioid response, but also
factors that may influence the perception and expression of pain.
It is important to remember thatpain expression does not necessarily correlate with nociception. Two patients with the same
etiology of pain causing similar nociception may perceive and express pain in a completely
different manner. Assessment of pain without a multidimensional approach ignores thecomplexity of the pain experience.
Two tools may assist the multidimensional assessment of pain. The Edmonton Symptom
Assessment System (ESAS)(38) measures nine symptoms using visual analogue scales: pain,
activity, nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath.
The ESAS is completed by the patient, if possible. It places pain in the context of other symptoms,
assesses outcomes of interventions and can be used to track individual patients over time. The
Edmonton Staging System (38) is a tool for identifying predictors of intractable pain such asneuropathic pain, incident pain, impaired cognitive functioning, major psychological distress,
opioid tolerance and history of drug or alcohol abuse. These assessment tools are particularly
useful to draw attention to patients who express their psychological, social or spiritual distress as
physical pain (somatization). Those patients are at risk of escalating their doses of opioids,
resulting in toxicity with little or no pain relief. This type of pain may improve with counseling,socialization, physical activity, or other distraction.
However, it is not sure if these assessment tools are applicable internationally since theexpression of pain as well as mood (anxiety/depression) may vary depending on patients’ cultural or
religious backgrounds (39).
Opioid hyperexcitability is often associated with delirium and probably does not have asingle common etiology. It is therefore important to consider correctable factors contributing todelirium. The etiology of delirium other than opioids may be follows: primary or metastatic
intracranial disease, metabolic encephalopathy, electrolyte imbalance, chemotherapy, steroids,
radiation, anticholinergics, antiemetics, antivirals, infection, nutritional deficiencies, paraneoplastic

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syndromes, etc. Theoretically, it is reasonable to treat these possible-contributing factors todelirium while observing the patient’s progress without switching the opioid. However there is an
ethical concern for potentially delaying definitive treatment in fragile advanced cancer patients withlimited life expectancy. Clinically, it is more beneficial for these patients to clear all the possible
aggravating factors in delirium and hyperexcitablity, particularly when the symptoms are severe.
Several strategies have been recommended to manage opioid-related hyperexcitability.
These include switching from one opioid to another, hydration, and reducing the opioid dose.
Reducing the opioid dose is only indicated when pain is well controlled in the presence of mild
opioid-related hyperexcitability. Hydration is advocated on the grounds that it promotes the renalelimination of opioid metabolites. A combination of rotating to an alternative opioid andhydration is often effective. The choice of opioid is, at the moment, empirical. While there may
be theoretical grounds to switch to an opioid with particular pharmacological properties, therelationship between experimental findings and clinical experience has not yet been established.
When considering opioid rotation, potency and equianalgesia are two important conceptsof opioid pharmacodynamics that require attention. Potency refers to the power of a medicinal
agent to generate its desired outcome that is the dose required to produce a given effect. A morepotent agent becomes beneficial when a limited volume is an issue, such as in subcutaneous
infusions (40). Equianalgesia refers to different doses of two agents that provide approximate pain
relief (40)(41).
Several equianalgesic dose tables are generally used to aid the clinician in converting fromone opioid to another. It has to be emphasized that much of the information in these tables has
been derived from single-dose studies that are more appropriate for the management of acute pain.
Only a limited number of studies have assessed opioid equianalgesic dose ratios in the context ofchronic pain management (41).
The bioavailability of each opioid, inter-individual or inter-racial genetic variability in themetabolism of each opioid, or incomplete cross-tolerance between opioids may play significantly
influence the equianalgesic dose ratio. It is therefore crucial to monitor clinically until stable pain
control and opioid doses have been achieved.
E. Conclusion
Opioid rotation has become a generally accepted practice for cancer pain relief
internationally. It is important to be aware of complexity of the pain experience and perform a
multidimensional assessment. Identifying potentially intractable pain and intervening in theirearlier stage may lead to successful pain relief. When opioid rotation is considered, excluding
other contributing factors for opioid neurotoxicity, and using appropriate equianalgesic dose ratioswith careful and close monitoring of patients’ pain and other symptoms are extremely important.
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EXPECTATIONS OF PERIPHERAL OPIOID ANALGESIA
J.G. Collins, Ph.D.
Professor of Anesthesiology
Lecturer in Pharmacology
Yale University School of Medicine

Dr. Collins will focus on the following points during this presentation: comparison of spinal opioid analgesia
with peripheral opioid analgesia; endogenous peripheral opioid analgesia; evidence for exogenous peripheral
opioid analgesia; possible mechanisms of action of peripheral opioid analgesia; questions that need to beanswered in order to better understand the potential for peripheral opioid analgesia as an important clinicaltool for the control of pain.
Ferreira and Nakamura first proposed the existence of peripheral opioid analgesia in 1979 (1) and other labs
reported similar findings almost ten years later (2,3). However those basic science studies did not produce asignificant use of peripheral opioid analgesia in the clinical setting. There is disappointment that peripheral
opioid analgesia has not become a widely used clinical tool with which to control pain. The limited use of
peripheral opioid analgesia is contrasted with spinal or epidural opioid administration. Dr. Collins willcompare the development of the two techniques and point out that such a comparison is not fair. The timingof each discovery as well as the types of pain against each can be effective differs greatly.
Stein and Colleagues have continued to pursue an understanding of the endogenous systems that mediate
peripheral opioid analgesia in the absence of exogenously administered drugs. That work has produced adetailed understanding of the interactions between the immune and nervous system that appear to be
responsible for a peripheral endogenous pain control system (4). An important consideration associated with
Stein’s work is the impact of a depressed immune system on a patient’s pain. It is likely that patients with acompromised immune system may experience greater levels of pain as a result of a dysfunctional peripheral
opioid analgesic system.
Although Stein and colleagues have firmly established the existence of an endogenous peripheral opioid
analgesia system we are still left with questions about the possibility of influencing that system byexogenously administered opioids. Several reviews have questioned the value of exogenous peripheral opioid
analgesia but they have also pointed out the significant problems that have been associated with most of theclinical trials in which the technique was examined (5-7). Because of the many problems with interpretationof most clinical trials of peripheral opioids, including lack of sensitivity of assays and inappropriate drug
doses, we still do not know the true potential value of the technique but it does offer unique advantages thatwarrant further study. Those advantages direct targeting to sites of inflammation and possible efficacy
against visceral pain, a type of pain that is difficult to treat with current methodologies.
There is evidence that the binding of opioids with opioid receptors on the peripheral terminals of primarysensory neurons causes changes in the functioning of the neurons that could impede the flow of informationfrom the periphery to the central nervous system. Changes in G proteins and ion channels have been reported(8-10). Such changes could reduce the excitability of peripheral nerves, decrease the propagation of action
potential sand reduce the peripheral release of pain producing substances. Those systems should also besensitive to exogenously administered opioids.
Essential questions that remain to be answered about peripheral opioid analgesia include what happens to thereceptors on nerve terminals to allow them to become sensitive to opioids and what is the nature of those
receptors. Although inflammation is required to enable peripheral opioid analgesia it can also be induced by a
hyper tonic solution. There appears to be receptor up-regulation but the time-course is much slower than the179

onset of peripheral opioid analgesia. We know that mu, delta and kappa opioid receptors exist on the
peripheral terminals of primary sensory neurons but we do not know if those receptors are the same as opioid
receptors that have been studied in the central nervous system. In fact, there is reason to believe that there aredifferences in peripheral opioid receptors that may cause them to have a different pharmacological profile
than classical central nervous system receptors (11, and Collins and colleagues, unpublished observations).
Answers to these questions are likely to enable us to determine the maximum efficacy of peripheral opioid
analgesia.
It is likely that we will be able to utilize the endogenous peripheral opioid system to produce a degree ofanalgesia that is greater than that caused naturally. We need to better understand how to unmask peripheral
opioid receptors and we also need to have a better understanding of the peripheral receptors themselves. In
addition we need the continuing support of drug development companies. It is likely that the most important
advance in peripheral opioid analgesia will depend on the development of novel agonists with high affinity
for peripheral receptors. Those agonists will also need to be restricted in their ability to gain access to thecentral nervous system. The potential value of peripheral opioid analgesia, in spite of current disappointment
in its progress, warrants a continued effort to understand and develop the technique for clinical pain
management.

1. Prostaglandins 18, 91-100, 1979
2. Anesth.Analg. 66, 1277-1281, 1987
3. Pharmac. Biochem. Behav. 31, 445-451, 1988
4. J. Neurosci. 22, 5588-5596, 2002
5. Pain 71, 127-134, 1997
6. Pain 72, 309-318, 1997
7. Anesth.Analg. 93, 761-770, 2001
8. Neuroscience 32, 571-575, 1989
9. J. Neurosci. 19, 8337-8348, 1999
10. Br. J. Pharmacol. 129, 110-114, 2000
11. Pain 79, 175-185, 1999180

在宅ホスピス・緩和ケアにおける疼痛緩和の実際と問題点
ホームケアクリニック川越院長 川越 厚
在宅ホスピス・緩和ケアでは患者の普段の生活を第一に考え、自然な形の経過を見ながら疼痛などの患者の苦痛を緩和し、患者と家族が安心して在宅で過ごせるような安全な方
法で医療を提供することが重要である。症状緩和の中心は疼痛緩和であり、その中心となる薬剤は strong opioid である。病院などの施設と違い在宅ではオピオイド使用に関してさ
まざまな制約と問題点があり、今回このような視点にたって当クリニックで関わった末期
癌患者の疼痛緩和を紹介するとともに、その問題点について述べることにする。
当院は開業 3 年目の無床診療所であるが、在宅末期癌患者に対するホスピス・緩和ケア
はグループ・バリアンを組織して学際的なチームケアの形をとってサービス提供している。
平成 12 年 7 月から同 14 年 6 月までの 2 年間に 177 例の末期癌患者を在宅でケアし、死亡した 146 名のうち 140 名（95.9%）は在宅死であった。在宅死した 140 例の中でモルヒネなどの strong opioid を使用したのは 99 例（71%）であり、そのうち 80 例（57%）はモル
ヒネ徐放剤経口投与、44 例（31%）は経直腸投与、28 例（20%）は持続皮下投与、2 例（1%）
が IVH 投与、1 例（1%）がフェンタニルパッチ投与であった。
在宅でのオピオイド使用に関する問題は①どのように説明して新規導入するか②オピオイド服用を誰が管理するか③DDS の変更（特に経口モルヒネ徐放剤から経皮的フェンタニル投与への変更）をどのように行うか、またその際どのような注意が必要か④臨死期に経口摂取が不可能となった時モルヒネ投与の継続をどのように考えたらよいか、また具体的な方法はどうあるべきか⑤モルヒネなどの廃棄方法はどうすればよいか⑥モルヒネの細やかな調整をどうすればよいか、などである。我々の対応の仕方を具体的な事例提示の中で明らかにしたい。

178