Negative pain management index scores do not necessarily indicate inadequate pain management: a cross-sectional study.

BACKGROUND: The Pain Management Index (PMI) is widely used in the assessment of pain management, and negative scores are traditionally considered to indicate inadequate pain management. However, it is not known whether negative PMI scores are always problematic. METHODS: In this prospective observational study, we examined the data of 1156 patients with cancer and pain who were hospitalized in a cancer care hospital in Japan from July 2012 to January 2015 and compared the proportion of patients with PI across various PMI scores in this cohort. We further evaluated the predictive validity of PMI scores for PI using different cutoffs. This study aimed to examine the association between PMI scores and the proportion of patients whose pain interferes with their daily lives (i.e., pain interference [PI]). RESULTS: We found that lower PMI scores were generally associated with a higher percentage of patients with PI. A smaller proportion of patients with PMI scores of - 1 (567/1550, 36.6%) reported PI compared with those with PMI scores of 0 (788/1505, 52.4%). The sensitivities of PMI scores < - 1 and < 0 for predicting PI were 0.16 and 0.37 and the corresponding specificities were 0.95 and 0.71, respectively. CONCLUSIONS: These findings suggest that PMI scores are inversely associated with the proportion of patients with PI. However, PMI scores of - 1 do not always indicate inadequate pain management; pain management should therefore be evaluated from multiple perspectives.

Efficacy and Safety of Oxycodone Injection for Relieving Cancer Pain: A Study in Japan Consisting of Two Open Trials for Intravenous and Subcutaneous Administration.

Pure oxycodone injection became increasingly necessary after oral oxycodone was launched in Japan in 2003. However, trials clarifying the efficacy and safety of injection are rare. Therefore, a multicenter open study on injection was designed and carried out in 2010, resulting in the launch of injection therapy in 2012. As published domestic case reports on efficacy already show widespread prescription, this study aimed to provide useful information for cancer pain relief in Japan and other countries. Our oxycodone injection study consisted of two trials, one of intravenous (S#9131) and the other of subcutaneous (S#9132) administration. The minimum required number of enrolled patients suffering cancer pain was determined to be 70 in S#9131 and 20 in S#9132. These studies had the same dose-titration protocol as the main endpoint, i.e., pain relief rate (PRR) defined as the rate of achieving adequate pain control (APC), as in prior oral oxycodone trials in Japan. In S#9131, PRR was 81.4% (95% confidence interval: 70.3-89.7%), therefore, the null hypothesis of PRR<70% was rejected using the binominal one-sided test (p=0.0217). In S#9132, PRR was 73.7% also surpassing 70%. Safety was also assessed in the same way as in prior trials. The majority of adverse effects were moderate or mild and recovered with no sequelae. As shown above, the injection was considered to be effective and safe in cancer pain treatment. The details of these trials, particularly the dose-titration protocol for achieving APC and route switching information, are expected to enhance injection convenience for prescribers.

How Do Hospital Palliative Care Teams Use the WHO Guidelines to Manage Unrelieved Cancer Pain? A 1-Year, Multicenter Audit in Japan.

It has been reported that pain relief for patients with cancer is suboptimal in Japan. This has been mainly attributed to inadequate dissemination of the World Health Organization (WHO) guidelines for cancer pain management. To better understand this problem, we reviewed how 6 hospital palliative care teams (HPCTs) used the WHO guidelines for unrelieved pain in a 1-year audit that included 534 patients. The HPCT interventions were classified according to the contents of the WHO guidelines. In our study, HPCT interventions involved opioid prescriptions in >80% of referred patients, and "For the Individual" and "Attention to Detail" were the 2 most important principles. Our study indicates which parts of the WHO guidelines should be most heavily emphasized, when disseminating them in Japan.

Accuracy of using Diagnosis Procedure Combination administrative claims data for estimating the amount of opioid consumption among cancer patients in Japan.

OBJECTIVE: The state of opioid consumption among cancer patients has never been comprehensively investigated in Japan. The Diagnosis Procedure Combination claims data may be used to measure and monitor opioid consumption among cancer patients, but the accuracy of using the Diagnosis Procedure Combination data for this purpose has never been tested. METHODS: We aimed to ascertain the accuracy of using the Diagnosis Procedure Combination claims data for estimating total opioid analgesic consumption by cancer patients compared with electronic medical records at Aomori Prefectural Central Hospital. We calculated percent differences between estimates obtained from electronic medical records and Diagnosis Procedure Combination claims data by month and drug type (morphine, oxycodone, fentanyl, buprenorphine, codeine and tramadol) between 1 October 2012 and 30 September 2013, and further examined the causes of discrepancy by reviewing medical and administrative charts between April and July 2013. RESULTS: Percent differences varied by month for drug types with small prescription volumes, but less so for drugs with larger prescription volumes. Differences also tended to diminish when consumption was compared for a year instead of a month. Total percent difference between electronic medical records and Diagnosis Procedure Combination data during the study period was -0.1% (4721 mg per year per hospital), as electronic medical records as baseline. Half of the discrepancy was caused by errors in data entry. CONCLUSION: Our study showed that Diagnosis Procedure Combination claims data can be used to accurately estimate opioid consumption among a population of cancer patients, although the same conclusion cannot be made for individual estimates or when making estimates for a group of patients over a short period of time.

Breakthrough pain management using fentanyl buccal tablet (FBT) in combination with around-the-clock (ATC) opioids based on the efficacy and safety of FBT, and its relationship with ATC opioids: results from an open-label, multi-center study in Japanese cancer patients with detailed evaluation.

OBJECTIVE: Rapid analgesic onset opioids, particularly fentanyl buccal tablet, is preferable for managing breakthrough pain. The efficacy and safety of fentanyl buccal tablet and its association with around-the-clock opioids needs to be explored with an option of dose adjustments, more closely reflecting administration in clinical practice. The aim of the study was to assess the safety and efficacy of fentanyl buccal tablet in breakthrough pain management in combination with around-the-clock opioids with the dose adjustment option, and explore the dose adjustment's influence on breakthrough pain management using detailed evaluation. METHODS: The 12-week open-label, multi-center study was conducted throughout Japan. Cancer patients aged 20 years or older, experiencing persistent pain controlled with around-the-clock opioids and breakthrough pain with supplemental medications were enrolled. Fentanyl buccal tablet and around-the-clock opioid doses could be adjusted under protocol-specified conditions. Efficacy variables were assessed at each fentanyl buccal tablet administration. Safety was assessed mainly by adverse events. RESULTS: All efficacy variables showed sustained analgesic effect. Nearly half the patients stayed on the same dose; most fentanyl buccal tablet administrations did not require additional supplemental medications. Dose increase of fentanyl buccal tablet and around-the-clock opioids seemed to improve breakthrough pain intensity and frequency, respectively. Fentanyl buccal tablet and around-the-clock opioid doses were not strongly associated. Treatment-related adverse events were all common with opioid treatment and did not increase over time. CONCLUSIONS: Fentanyl buccal tablet can stably and safely manage breakthrough pain in cancer patients with independent dose adjustment based on detailed evaluation of each patient's condition. Breakthrough pain management using fentanyl buccal tablet with around-the-clock opioids at optimal doses may be an important factor in palliative care for cancer patients with breakthrough pain.

Pharmacokinetics of oxycodone after intravenous and subcutaneous administration in Japanese patients with cancer pain.

ABSTRACT In Japan, Oxycodone hydrochloride injection formulation has been approved in 2012. However, its pharmacokinetics has been poorly studied. The aim of this study is to evaluate the pharmacokinetics of oxycodone after intravenous and subcutaneous administration of oxycodone hydrochloride injection in Japanese patients with cancer pain. Noncompartmental analysis and population pharmacokinetic analysis were performed. We conducted a multicenter open-label study of oxycodone hydrochloride administered as constant infusion with the dose titrated individually according to the pain intensity in patients with cancer pain. Pharmacokinetic parameters for plasma oxycodone and its metabolites were estimated using pharmacokinetics of oxycodone was evaluated using a total of 344 plasma concentrations obtained from 89 patients. The estimated geometric mean clearance (CL) of oxycodone was 24.3 L per hour after constant intravenous infusion and 29.5 L per hour after constant subcutaneous infusion, respectively. Population pharmacokinetic analysis indicated that body surface area was the influencing factor on CL and there were no pharmacokinetic differences for CL between intravenous and subcutaneous infusion. These results provide important information for the clinical use of oxycodone injection.

A randomized, double-blind, placebo-controlled study of fentanyl buccal tablets for breakthrough pain: efficacy and safety in Japanese cancer patients.

CONTEXT: Rapid-onset opioids for treating breakthrough pain (BTP) in patients with cancer are needed in the Japanese care setting. OBJECTIVES: To examine the efficacy and safety of fentanyl buccal tablets (FBTs) for treating BTP in Japanese cancer patients. METHODS: This was a randomized, double-blinded, placebo-controlled study. In subjects receiving around-the-clock (ATC) opioids at doses of 30 mg or more to less than 60 mg or 60-1000 mg of oral morphine equivalents (low and high ATC groups), dose titration was started from 50 to 100 µg FBT, respectively. Subjects whose effective dose was identified were randomly allocated to a prearranged administration order of nine tablets (six FBTs and three placebos), one tablet each for nine episodes of BTP (double blinded). Efficacy and safety of FBT were assessed for patients overall, and also for the low and high ATC groups. RESULTS: A significant difference was observed between FBT and placebo for the primary endpoint of pain intensity difference at 30 minutes. The analgesic onset of FBT was observed from 15 minutes in several secondary variables (e.g., pain relief). Adverse events were somnolence and other events associated with opioids were mostly mild or moderate. Of the low and high ATC group subjects, an effective FBT dose was identified in 72.2% and 73.1%, respectively. CONCLUSION: The safety of FBT and its analgesic effect on BTP were confirmed in Japanese cancer patients receiving opioids. Our findings suggest that analgesic onset may occur from 15 minutes after FBT, and that FBT can be administered to patients with low doses of ATC opioids.

Prevalence of analgesic prescriptions among patients with cancer in Japan: an analysis of health insurance claims data.

OBJECTIVES: To promote effective management of cancer pain as a nationwide health policy, it is necessary to monitor the performance of health care providers in managing pain in their patients. To plan a system that monitors the performance of pain management, the exact Methods of measurement, including the range of target patients, and estimate the resources must be defined. Performance in pain management can be evaluated either in all patients with cancer or restricted to patients with cancer who are already taking analgesics. Restricting the target patient group to patients on analgesics may be more efficient but the extent of that efficiency remains uncertain. METHODS: Using insurance claims from eight employer-sponsored insurance companies, we analyzed data from patients (N = 2858) who had received anti-cancer treatment (ie, surgery, chemotherapy, and radiation therapy) for the five major cancers in Japan (ie, breast, colorectal, liver, lung, and stomach cancers). RESULTS: Overall, 22.9% of patients received some kind of analgesic prescription in the course of a month. Lung cancer patients were more likely to be prescribed analgesic prescriptions (any analgesics 34.8%; opioids 18.2%) than patients with the other four cancers. The observed percentage of patients who received analgesic prescriptions over the study period (ie, January 2005 to November 2009) decreased. CONCLUSION: If we limit the target patient group to patients with cancer already on analgesics, we can reduce the number of persons to be contacted by about three-fourths, compared to assessing pain in all patients with cancer. Although we do not wish to ignore the problem of undetected pain among patients with cancer, beginning our systematic evaluation with patients with cancer already on analgesics may be a realistic option.

[Efficacy and safety of compound oxycodone injection for cancer pain relief-a multicenter survey of prescriptions].

Oral oxycodone has been available since 2003 in Japan. Oxycodone consumption is increasing along with the decrease in morphine consumption. Although this drug currently has a central role in cancer pain treatment, at this time pure oxycodone injection has not yet been available in Japan. As an alternative, we can subcutaneously administer a compound oxycodone injection (Pavinal) containing a small amount of hydrocotarnine. Since few clinical reports on efficacy and safety of the compound oxycodone injection have been published in Japan, we conducted a retrospective multicenter survey with structured sheets. Monthly survey data regarding the compound prescriptions for cancer pain control have been collected from 3 cancer hospitals. Finally, sixty adult patients were analyzed with the following results. (1) The adverse effects caused by the prior opioids improved in more than half of the patients, and worsened in none. (2) Dose escalation of the drug was achieved through subcutaneous administration(the mean was 1.6 times), and resulted in pain relief with tolerable adverse effects in more than 80% of patients. (3) Adverse effects occurred in 13% of patients, but more than 80% of the episodes were mild in severity. Conversely, we found no adverse effects becoming sequelae, failure and/or fatal in severity. (4) Subcutaneous administrations with the drug were available in long-term(mean 15.4 days, maximum 53 days), including home palliative care use (1.7%). No toxicities due to accumulation were observed. (5) The conversion ratio from oral oxycodone to compound oxycodone injection was 0.82+/-0.20, and the domestic and international reports are basically consistent with our result. So we speculate that the compound can be regarded as a pure oxycodone injection using subcutaneous administration. While further studies are needed, our study indicated that compound oxycodone injection has efficacy and safety in cancer pain treatment. Especially in switching opioids and/or their routes of administration to enhance the analgesic potency along with reducing the adverse effect, we conclude that prescribing this drug can be a convenient alternative.

[Efficacy and safety of continuous subcutaneous injection of the compound oxycodone in cancer pain management: the first 4-year audit].

The compound oxycodone injection, but not pure oxycodone, has been available since the 1920's in Japan. The compound, containing oxycodone and hydrocotarnine, can be subcutaneously administered. Hydrocotarnine is a non-narcotic opium alkaloid. Nowadays, along with the increase in the prescription frequency of oral oxycodone, the compound oxycodone injection is regarded as an important alternative in palliative care. However, few clinical reports about this drug have been documented in Japan. We have intensively introduced the compound for cancer pain control since 4 years ago and we report a study on the safety and efficacy of the continuous subcutaneous administration of the compound injection. Ninety-seven patients were naively administered the compound for cancer pain control and the mean administered period was 18. 0+/-15. 5 days. 61. 9% of all cases were switched from oral oxycodone. The efficacy in cancer pain control was evaluated for the first two weeks using a numeric rating scale (NRS: 0, no pain, and 10, imaginary worst ). They had statically shown pain control improvement from 6. 8+/-2. 8 on administration to 2. 4+/-2. 5 one week later, 1. 7+/-1. 9 two weeks later, and 2. 3 +/-2. 6 on the last observation day of the study (p<0. 001). One week later on administration, no significant adverse effects were found in the serology, conscious level, and subjective symptoms of nausea and vomiting. But adverse effects difficult to manage were experienced in 7. 2%, including delirium, constipation, nausea and vomiting, vertigo, and local skin toxicity on the injected site. All episodes were experienced within 16 days of compound administration, which had been followed by switching to fentanyl or subcutaneous morphine injection. The conversion ratio from compound oxycodone injection to oral oxycodone was 1. 43 without adjustment required(n=35). We speculate that the compound can be regarded as a pure oxycodone injection using continuous subcutaneous administration. While our clinical audit is a primitive one, we may conclude that the continuous subcutaneous administration of the compound oxycodone injection should be effective and safe in clinical use for cancer pain control.

Baclofen as an adjuvant analgesic for cancer pain.

PURPOSE: Baclofen is a g-aminobutyric acid receptor agonist commonly used for managing many types of neuropathic pain. The effect of baclofen on cancer pain has not previously been studied. This retrospective study evaluated the efficacy of baclofen in patients with cancer pain. METHODS: We reviewed the medical records of all patients given baclofen orally as an analgesic for cancer at 5 institutions. RESULT: Twenty-five patients received 10 to 40 mg of baclofen for cancer pain relief. Twenty patients have undergone neuropathic pain such as paroxysmal or lancing, sharp, or like an electric shock. Baclofen was effective in 21 of 25 patients and significantly reduced Numeric Rating Scale (pain score, 0-10; P < .0001). Nine patients reported mild adverse events: none of these 9 patients had to discontinue baclofen due to adverse events. CONCLUSION: Our findings suggest that baclofen may be a useful adjuvant analgesic in the treatment of cancer pain.

[Validity of recommended minimum dose of prior morphine to initiate transdermal fentanyl patch in prescribing information - multicenter survey of on prescriptions by palliative care specialists in Japan].

For initiating the minimum-size (0.25 microg/hour) transdermal fentanyl patch (TDF), 45 mg a day of oral morphine is the recommended minimum dose (RMD) in Japan according to the prescribing information. However, little is known about the validity of the RMD, and we can presume there are many cases where clinicians are inclined to initiate the minimum-size TDF at the early stage contrary to the RMD due to the high morbidity rate of digestive system cancer in Japan. In order to verify the validity of the RMD, we collected 71 retrospective cases where the minimum-size TDF was initiated against the restriction of RMD. The prior morphine (or equivalent doses of other opioids) was prescribed by palliative care specialists at 5 facilities which belong to Symptom Control Research Group (SCORE-G). Then, the side effects and pain control from the 1st to the 4th day were analyzed. The mean age of subjects was 68, and the main reason for initiating TDF therapy was gastrointestinal symptoms (63.4%). The frequency of side effects such as somnolence, nausea, vomiting and constipation did not show a significant correlation with the prior opioid dose.However,severe dyspnea and respiration depression were documented in two patients, and the above rate was three times higher than the nationwide result of the same side effects (0.9 8%). According to the Numeric Rating Scale (from 0: no pain to 10: the worst pain), the pain intensity decreased from 6.6 on the 1st day to 2.8 on the 2nd day, 3.3 on the 3rd day, and 2.9 (p < 0.001) on the 4th day. We conclude that, although introducing the minimum-size TDF against the RMD served to decrease the pain intensity,it raised the side effects on the respiratory system even when prescribed by palliative care specialists. Therefore,the RMD regulation is valid for general practitioners from a medical safety standpoint.

[A rare case of disseminated Mycobacterium kansasii infection].

Mycobacterium kansasii infection has been reported to be about 20 percent of non-tuberculous mycobacteriosis, and its disseminated type is uncommon and the prognosis is reported to be generally poor. We experienced one case of disseminated Mycobacterium kansasii infection. A 81 year-old man who had been short-bowel syndrome due to the operation for superior mesenteric artery occlusion since 1998 was admitted on April 24th, 2001 to our hospital because of slowly progressive consciousness disturbance and anorexia. He had shown progressive productive cough and respiratory failure and laboratory findings were C-reactive protein elevation and pancytopenia. Human immunodeficiency virus (HIV) antibody was negative. Chest X-ray and computed tomography showed diffuse miliary nodules and infiltrative shadow. Sputum examination was positive for mycobacteria. The cultured isolate was identified as Mycobacterium kansasii. Bone marrow aspirations revealed inflammatory granuloma with necrosis. He was diagnosed as disseminated Mycobacterium kansasii infection and heart failure, and was treated by anti-tuberculosis drugs and diuretics. Treatment was very effective and Chest X-ray findings and respiratory failure had been completely improved. In this case we speculated that the malnutrition due to short-bowel syndrome could be one of the most suspected reasons of Mycobacterium kansasii dissemination. Disseminated Mycobacterium kansasii infection has been rarely reported comparing with the other mycobacterial infections in Japan. However, due to the increasing numbers of immunocompromised hosts with aging, HIV infection, cancer, and steroid therapy, this type of infection will become more common and its earlier diagnosis and adequate treatment will be important to improve the prognosis.