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.

Role of dopamine D2 and D3 receptors in mediating the U-50,488H discriminative cue: comparison with methamphetamine and cocaine.

Substitutions of the dopamine D(2) or D(3) receptor agonists for the discriminative stimulus effect induced by U-50,488H, methamphetamine (METH) and cocaine in rats were examined. The D(2) receptor agonist R-propylnorapomorphine [(-)-NPA] failed to substitute for U-50,488H cue, while the D(3) receptor-preferred agonist (+/-)-7-hydroxy-dipropylaminotetralin hydrobromide (7-OH-DPAT) produced dose-related increases in drug-appropriate responding up to 0.03 mg/kg, which fully substituted. At doses greater than 0.03 mg/kg of 7-OH-DPAT, there was a dose-dependent decrease in the percentage of responses on the U-50,488H-appropriate lever. Furthermore (-)-NPA and 7-OH-DPAT at high doses substituted for the discriminative stimulus effect induced by both METH and cocaine, indicating that 7-OH-DPAT at high doses may interact with D(2) receptors. These results suggest that the stimulation of D(2) receptor may be critical for the production of the discriminative stimulus effect induced by METH and cocaine, whereas the stimulation of D(3) receptor may contribute to the production of the U-50,488H cue.

Enhancement of glutamatergic transmission in the cingulate cortex in response to mild noxious stimuli under a neuropathic pain-like state.

Pain is evoked by noxious body stimulation or through negative emotional events and memories. There are several caveats to the simple proposition that pain and emotion are linked in the cingulate cortex (CG). In this study, we investigated whether mild noxious heat stimuli could affect the neuronal activity in the CG of rats with sciatic nerve ligation. We produced a partial sciatic nerve injury by tying a tight ligature in rats. Seven days after sciatic nerve ligation, rats received mild noxious heat stimuli. Mild noxious heat stimuli produced flinching behaviors in sciatic nerve-ligated rats, but not sham-operated rats. In addition, the mild noxious heat stimuli caused a significant increase in the release of glutamate in the CG of nerve-ligated rats compared with that of sham-operated rats. Furthermore, phosphorylated-NR1-positive cells in this area significantly increased after mild noxious heat stimuli under a neuropathic pain. Under this condition, there were no significant changes in the levels of immediate-early genes such as c-fos, c-jun, JunB, and Fra1 in the CG between nerve-ligated and sham-operated rats. However, mild noxious heat stimuli under a neuropathic pain-like state produced a marked increase in the phosphorylated-c-jun (p-c-jun) immunoreactivity, which is commonly used to map neurons in the brain that can be activated after N-methyl-D-aspartate receptor activation. These findings raise the possibility that mild noxious heat stimuli under a peripheral nerve injury may increase the release of glutamate and promote its related postneuronal activity in the CG.

[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.

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.

Epidural ropivacaine infusion for the treatment of pain following axillary muscle-sparing thoracotomy: a dose-evaluation study.

PURPOSE: We aimed to investigate the optimal dose of continuous epidural ropivacaine for effective analgesia with minimal side effects after axillary muscle-sparing thoracotomy. METHODS: Sixty patients undergoing thoracic surgery via the axillary approach were studied. Patients were given continuous epidural ropivacaine at 6 (group R-6), 9 (group R-9), 12 (group R-12) or 18 mg x h(-1) (group R-18) in a randomized double-blinded fashion after surgery. All of the patients received nonsteroidal anti-inflammatory drugs (NSAIDs) every 6 h for 24 h postoperatively. Pain intensity was assessed under three conditions (at rest, on moving, and while coughing), at 4, 8, 16, 24, and 48 h after surgery, and the extent of sensory block was evaluated at the same time points. The ability of a patient to walk unaided was assessed at 24 and 48 h after surgery. RESULTS: Pain intensity at rest and coughing was significantly higher in group R-6 than in the other groups at 16 h after surgery. Pain intensity during moving was significantly greater in group R-6 than in groups R-12 and R-18 at 16 h after surgery. Group R-18 exhibited a significantly greater extent of sensory block than the other groups. The number of patients who were not able to walk unaided 24 h after surgery was significantly greater in group R-18. There were no significant differences in the incidences of side effects among the groups. CONCLUSION: Our results showed that epidural analgesia using ropivacaine, at 12 mg x h(-1), provided the best analgesia with few side effects.

[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.

Evaluation of allodynia and pain associated with postherpetic neuralgia using current perception threshold testing.

OBJECTIVES: Postherpetic neuralgia has various clinical features, and the implicated pathophysiologic mechanisms are controversial. This study was carried out to clarify the roles of peripheral sensory nerves in the production of allodynia and ongoing pain. Current perception threshold (CPT) testing was used to evaluate the sensory function. METHODS: The intensities of ongoing pain and dynamic allodynia were assessed using a numeric rating scale (0-10). Assessment of sensory nerve function was performed by a series of 2,000-, 250-, and 5-Hz stimuli using CPT testing. These measurements were made in ipsilateral and contralateral area. RESULTS: CPTs at all frequencies in the ipsilateral area were significantly higher than those in the contralateral area. There were significant and inverse correlations between the intensity of allodynia and CPTs at all frequencies. No correlation was found between the intensity of ongoing pain and CPTs at any frequency. There was no correlation between the intensity of ongoing pain and the intensity of dynamic allodynia. CONCLUSIONS: The intensity of dynamic allodynia in postherpetic neuralgia correlates with the preserved functions of Abeta, Adelta, and C fibers. In contrast, the intensity of ongoing pain does not correlate with either the preserved function of C fibers or the intensity of dynamic allodynia. Therefore, it is suggested that postherpetic neuralgia might be a pain syndrome including both peripheral and central mechanisms.

Cardioprotective effects of KB-R7943, a novel inhibitor of Na+/Ca2+ exchanger, on stunned myocardium in anesthetized dogs.

PURPOSE: The present study was carried out to determine the cardioprotective effects of KB-R7943 (KBR), a selective inhibitor of the reverse mode of Na+/Ca2+ exchanger (NCX), on stunned myocardium in anesthetized dogs. METHODS: The dogs were allocated to one of three groups (n = 7 for each group), and received drug vehicle (group C), low-dose KBR (5 mg x kg(-1) i.v.) (group L) or high-dose KBR (10 mg x kg(-1) i.v.) (group H) at 15 min before left anterior descending coronary artery (LAD) occlusion. Stunned myocardium was produced by 15-min occlusion of LAD and 90-min reperfusion in all dogs. Regional myocardial contractility was evaluated with segment shortening (%SS). RESULTS: Recovery of %SS at 90 min after reperfusion was significantly improved in group H (70.8% +/- 3.9% of baseline), whereas the recovery was poor in groups C and L (34.3% +/- 2.8% and 36.4% +/- 5.4% of baseline, respectively). Regional myocardial blood flow showed no significant difference among groups. KBR had no effect on coronary or systemic hemodynamics. CONCLUSION: The results show that preischemic administration of high-dose KBR markedly improves myocardial contractile dysfunction after ischemia-reperfusion in anesthetized dogs, indicating that KBR protects myocardium against the ischemia-reperfusion injury in vivo.

Negative inotropic action of propofol is enhanced in the acute ischemic myocardium of dogs.

PURPOSE: We investigated the effects of propofol on contractility and oxygen balance in acute ischemic myocardium and compared them with those of normal myocardium using a coronary microembolization model in dogs. METHODS: In open-chest dogs, the left anterior descending coronary artery (LAD) was perfused through an extracorporeal bypass from the carotid artery. Regional myocardial contractility and myocardial oxygen balance were evaluated along with segment shortening (%SS), regional myocardial oxygen consumption (MVO2), and lactate extraction ratio (LER) of the area perfused by the LAD. Acute ischemia was produced by repeated injection of microspheres into the LAD-perfused area until %SS decreased by 50% of baseline. RESULTS: In normal myocardium, intracoronary infusion of propofol at doses of 1.2 and 2.4 mg x kg(-1) x h(-1) caused slight decreases in %SS to 83% +/- 8% and 80% +/- 10%, respectively. In ischemic myocardium, propofol caused greater decreases in %SS (59% +/- 18% and 35% +/- 20%, respectively). The changes in MVO2 after propofol infusion generally paralleled the changes in %SS, but LER was not changed in either ischemic or normal myocardium. CONCLUSION: Propofol causes a greater decrease in the contractility of acute ischemic myocardium as compared with normal myocardium in which myocardial oxygen imbalance is not involved as a mechanism.

The effects of dexmedetomidine on left ventricular function during hypoxia and reoxygenation in isolated rat hearts.

Hypoxia resulting from apnea in patients with sleep apnea is an important factor in heart disease. We designed the present study to determine whether dexmedetomidine (DEX) has a direct protective effect against hypoxia-reoxygenation-induced left ventricular dysfunction without systemic hemodynamic and humoral effects. Isolated rat hearts were exposed to 60-min hypoxia followed by 30-min reoxygenation with 0, 10, or 100 nM DEX prehypoxia administration (n = 7 each group). In a second experiment (n = 7), 100 nM DEX was administered posthypoxia. In a third experiment (n = 7 each group), an alpha 2 antagonist, yohimbine was given with and without 100 nM DEX prehypoxia administration. DEX prehypoxia, but not posthypoxia, administration significantly improved the recovery of left ventricular developed pressure after reoxygenation (0, 10, 100 nM DEX prehypoxia or 100 nM DEX posthypoxia values were 53 +/- 6, 64 +/- 9, 78 +/- 13, or 62 +/- 12 mm Hg [mean +/- sd]) and reversed by yohimbine, 58 +/- 8 mm Hg, respectively. We conclude that DEX exerts the direct protective effect on the left ventricular dysfunction caused by hypoxia-reoxygenation through mainly alpha 2-adrenergic stimulation before and during the hypoxic period.

Multiple sclerosis with severe pain and allodynia alleviated by oral ketamine.

The objective of this study is to determine the effect of oral ketamine on pain and allodynia associated with multiple sclerosis. A 60-year-old woman with multiple sclerosis was referred to our clinic because of severe pain and allodynia. Oral ketamine was started at a dose of 20 mg once a day and increased to twice a day. Oral ketamine was effective in the treatment of the pain and allodynia associated with multiple sclerosis.

The interaction of MCI-154, a calcium sensitizer, and isoflurane on systemic and coronary hemodynamics in chronically instrumented dogs.

UNLABELLED: We conducted this study to determine the interaction of MCI-154, 6-[4-(4'-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride, a calcium sensitizer, and isoflurane on myocardial contractility as well as systemic and coronary hemodynamics in chronically instrumented dogs after pharmacological autonomic nervous system activity blockade. MCI-154 increased heart rate and left ventricular function with no change in rate pressure product, pressure work index, and coronary blood flow, with a decrease in coronary vascular resistance (CVR) in the conscious state. Isoflurane decreased heart rate and left ventricular function, with a decrease in rate pressure product and pressure work index. Isoflurane also decreased CVR, but not coronary blood flow. The cardiovascular actions of MCI-154 during isoflurane anesthesia were qualitatively similar to those observed in the conscious state. In contrast to the finding in the conscious state, MCI-154 reversed the decrease in cardiac output and preload recruitable stroke work caused by isoflurane, but these are not significantly different from the effects of isoflurane alone. These results indicate that MCI-154 increases myocardial contractility and decreases CVR without changing calculated myocardial oxygen consumption during both the conscious state and isoflurane anesthesia. IMPLICATIONS: MCI-154, a calcium sensitizer, restores the myocardial contractility depressed by isoflurane and enhances the coronary vasodilating effect of isoflurane in chronically instrumented dogs.

Quantitative and selective evaluation of differential sensory nerve block after transdermal lidocaine.

UNLABELLED: We evaluated the effect of transdermal lidocaine on differential sensory nerve block in 15 healthy volunteers. Lidocaine 10% gel was applied topically to a forearm and covered with a plastic film. Three types of sensory nerve fibers (Abeta, Adelta, and C fibers) were evaluated with a series of 2000-, 250-, and 5-Hz stimuli using current perception threshold (CPT) testing. Sensations of touch, pinprick, cold, and warmth were also measured. These measurements were made before the topical lidocaine (baseline), 60 min after the draping (T0), and at 1-h intervals until 5 h after T0 (T1 to T5). A significant increase in CPT compared with baseline was observed until T2 at 5 Hz and T4 at 250 Hz, whereas the increase in CPT at 2000 Hz continued throughout the study period. All subjects experienced the disappearance of pinprick and cold sensations, whereas touch and warmth sensations were detectable during the study period. We conclude that when lidocaine is applied transdermally, the sensitivity of nerves to local anesthetics is proportional to the axon diameters. However, pinprick and cold sensation are affected more strongly than other sensations at receptor sites. IMPLICATIONS: We evaluated the effect of transdermal lidocaine on differential sensory nerve block in healthy volunteers. Our results show that the sensitivity of nerves to local anesthetics is proportional to the axon diameter.

A comparative evaluation of transcutaneous and end-tidal measurements of CO2 in thoracic anesthesia.

We performed this study to assess the accuracy of transcutaneous CO(2) (PTCCO(2)) monitoring compared with end-tidal CO(2) (PETCO(2)) in thoracic anesthesia. Twenty-six patients undergoing pneumonectomy with thoracotomy for which a long period of one-lung ventilation (OLV) was required were studied. The lungs were mechanically ventilated in the lateral decubitus position. PTCCO(2), PETCO(2), and arterial CO(2) (PaCO(2)) were simultaneously measured during two-lung ventilation (TLV) and during OLV at intervals of 15 min. All patients completed the study protocol. Bland-Altman analysis revealed a bias of -0.4 mm Hg with a precision of +/-2.5 mm Hg during OLV and 1.4 mm Hg with +/-4.3 mm Hg during TLV when PTCCO(2) and PaCO(2) were compared and revealed a bias of -5.8 mm Hg with a precision of +/-4.1 mm Hg during OLV and -7.1 mm Hg with +/-4.6 mm Hg during TLV when PETCO(2) and PaCO(2) were compared. We conclude that PTCCO(2) monitoring is accurate for evaluating CO(2) levels during thoracic anesthesia.

Hemodynamic interactions of propofol and dantrolene in chronically instrumented dogs.

UNLABELLED: The hemodynamic interaction of dantrolene, a specific drug for malignant hyperthermia, and propofol which appears to be safe in malignant hyperthermia-susceptible patients, has not been investigated. We performed this study to examine the hemodynamic actions of dantrolene at a therapeutic dose during propofol anesthesia. Ten dogs were chronically instrumented for the measurements of systemic and coronary hemodynamics. The dogs were assigned to receive propofol with vehicle or dantrolene in a random manner on separate experimental days. Propofol significantly decreased mean arterial blood pressure, left ventricular systolic and end-diastolic pressure, the maximal rate of increase in left ventricular pressure, and left ventricular regional segment shortening. Coronary blood flow (CBF) was unchanged but coronary vascular resistance (CVR) decreased. Dantrolene reversed the decrease in mean arterial blood pressure and left ventricular systolic pressure caused by propofol, and significantly increased heart rate. However, left ventricular end-diastolic pressure, cardiac output, maximal rate of increase in left ventricular pressure, and segment shortening were unchanged. CBF was significantly increased with a decrease in CVR. These results suggest that dantrolene reverses the hypotensive action produced by propofol and causes an increase in CBF with a decrease in CVR, but does not significantly change the negative inotropic effects. Thus, dantrolene exerts favorable hemodynamic effects during propofol anesthesia. IMPLICATIONS: Our study suggests that dantrolene reverses the hypotensive action produced by propofol and causes an increase in coronary blood flow with a decrease in coronary vascular resistance, but does not significantly change the negative inotropic effects.

Effect of ONO-1101, a novel short-acting ß-blocker on hemodynamic responses to isoflurane inhalation and tracheal intubation.

PURPOSE: We investigated the effect of a new ultrashort-acting ß-blocker, ONO-1101, on hemodynamic responses to isoflurane inhalation and tracheal intubation. METHODS: Fifty-four ASA PS 1 or 2 patients were randomly allocated to receive either ONO-1101, 0.04 mg·kg-1·min-1, or saline prior to tracheal intubation. Anesthesia was induced with thiamylal, 4 mg·kg-1, and vecuronium, 0.15 mg·kg-1. Tracheal intubation was carried out after 3 min controlled mask ventilation with 66% N2O and 3% inspired isoflurane in oxygen. Heart rate and blood pressure were continuously recorded from the start of induction until 5 min after intubation. Plasma concentrations of catecholamines were measured before induction, 3 min after initiating inhalation of isoflurane, and 1 min after tracheal intubation. RESULTS: Significant increases in heart rate occurred in both groups in response to isoflurane inhalation and tracheal intubation, but the magnitude of the increase was significantly less in the ONO-1101 group. Blood pressure increased after tracheal intubation in the saline group but remained unchanged in the ONO-1101 group. Plasma concentrations of norepinephrine increased after induction and intubation in both groups, with no significant difference between the groups. CONCLUSION: ONO-1101 infusion is effective for the attenuation of hemodynamic responses to isoflurane inhalation and tracheal intubation.