Efficacy and safety of sublingual fentanyl orally disintegrating tablet at doses determined by titration for the treatment of breakthrough pain in Japanese cancer patients: a multicenter, randomized, placebo-controlled, double-blind phase III trial.

BACKGROUND: Breakthrough cancer pain typically has a rapid onset and relatively short duration. Due to this temporal profile, it may not be adequately relieved by oral opioid analgesics. The sublingual fentanyl orally disintegrating tablet is a formulation by which fentanyl can be rapidly absorbed across the oral mucosa producing rapid-onset analgesia, and which may be effective for breakthrough pain treatment. METHODS: A multicenter, randomized, placebo-controlled, double-blind comparative study was conducted to evaluate the efficacy and safety of the sublingual fentanyl tablet at optimized doses for breakthrough pain treatment in cancer patients treated with strong opioid analgesics at fixed intervals. The optimal dose was determined by open-label dose titration. The efficacy and safety of a 12-week extended treatment were also evaluated. RESULTS: Eleven of 42 subjects who received the sublingual fentanyl tablet experienced adverse drug reactions. Common reactions were somnolence, constipation, nausea, and vomiting. No serious adverse reactions occurred. Sublingual fentanyl tablets at optimal doses and placebo were administered to 37 subjects in a double-blinded manner. A significant analgesic effect of the sublingual fentanyl tablet was present compared to placebo at 30 min after administration. The sublingual fentanyl tablet was also effective and safe during extended treatment, in which changes in basal opioid doses as well as sublingual fentanyl tablet doses were made as needed. CONCLUSION: Sublingual fentanyl tablets at doses determined by titration were effective and safe for breakthrough pain treatment in cancer patients treated with strong opioid analgesics at fixed intervals. Extended treatment up to 12 weeks was also effective and safe.

Atropine eyedrops for death rattle in a terminal cancer patient.

"Death rattle" is a term used to describe the noisy sound produced by dying patients caused by the oscillatory movements of secretions in the upper airways. Antimuscarinic drugs, including atropine, scopolamine (hyoscine hydrobromide), hyoscine butylbromide, and glycopyrronium, have been used to diminish the noisy sound by reducing airway secretions. We report on the effectiveness of sublingual atropine eyedrops in alleviating death rattle in a terminal cancer patient. We present a 58-year-old man with pancreatic cancer who was admitted to our hospital because of severe dyspnea, cough, and death rattle with excessive bronchial secretion as a result of multiple lung metastases. We administered 1% atropine eyedrops sublingually to obviate the need for subcutaneous infusions and to prevent somnolence. On the basis of our experience, we conclude that atropine eyedrops, administered sublingually for distressing upper respiratory secretions, may be an effective alternative to the injection of antimuscarinic drugs, or as an option when other antimuscarinic formulations are not available.

Palmar petechiae (black spots on palms) in terminally ill patients with cancer: a sign of impending death.

Certain physical signs can be useful in predicting impending death. We present four terminally ill patients with malignancy who developed petechiae on their bilateral palms and fingers during the week prior to their deaths. Drug-induced eruption, injury, and mechanical stimuli were thought to be unlikely causes of the petechiae. While the phenomenon has not previously been reported, we speculate palmar petechiae may be a clinical cutaneous sign of systemic deterioration in terminally ill patients.

Treatment of malignant enterovesical fistula with octreotide.

Surgical treatment for internal fistula is rarely indicated for terminally ill patients with cancer because of their poor prognoses. Reports of surgical or pharmacologic treatment of vesicoenteric fistula in terminally ill patients with cancer are rare. A 73-year-old woman with rectal cancer that had directly invaded the bladder and metastasized to the liver was admitted to our hospital with high fever and severe perineal pain. Retrograde urography indicated an enterovesical fistula. Although the urinary tract infection was treatable with antibiotics, frequent episodic pain, due to urethritis secondary to the fistula, was not alleviated with opioid and topical treatment. Three days after starting octreotide 0.3 mg/d, the severe pain was alleviated, and follow-up retrograde urography revealed closure of the fistula. This suggests that treatment with octreotide may have enabled closure of the fistula. Thus, octreotide should be considered a viable therapeutic option in terminally ill patients with inoperable internal fistula.

[Gabapentin mitigates neuropathic pain in cancer patients--a case report].

A 64-year-old male underwent low anterior resection of the rectum for rectal cancer. Five years later, he suffered neuropathic cancer pain on the left-posterior surface of his thigh caused by sacral invasion of the recurrence site. His neuropathic pain was not sufficiently responsive to the combination therapy of opioids, non-steroidal antiinflammatory drugs (NSAIDs), continuous infusion of subcutaneous ketamine and oral mexiletine. Gabapentin, which has been suggested as an adjuvant analgesic for neuropathic pain introduced orally, rapidly and significantly alleviated his pain and we could subsequently dispense with ketamine and mexiletine. No adverse effect was seen during this treatment. The present case indicates that gabapentin would be one of the most effective adjuvant analgesics for neuropathic cancer pain.

[Efficacy of controlled-release oxycodone for dyspnea in cancer patients--three case series].

Dyspnea is a common symptom in patients with advanced cancer. Systemic morphine administration has been reported as an effective pharmacological treatment to control dyspnea. However, there have been few reports on similar effects of alternative opioids except for morphine. To evaluate the effect of controlled-release oxycodone on the relief of dyspnea, we investigated three cases with opioid substitution from subcutaneous morphine to oral oxycodone. In all cases, both opioids provided equivalent effects for the palliation of cancer dyspnea with no significant adverse effects. Future studies in the appropriate clinical designs will be needed to confirm our findings.

[Olanzapine use in cancer patients for refractory vomiting].

Recent investigations suggest the efficacy of olanzapine in cancer patients with intractable vomiting or chemotherapy-induced nausea. Olanzapine,indicated for schizophrenia in Japan, has an affinity for multiple neurotransmitter receptors including dopaminergic, serotonergic, histaminergic, adrenergic and muscarinic receptors. This pharmacological activity thus has a potential role in the treatment of nausea and vomiting. In the present study, olanzapine was given to five cancer patients with refractory vomiting to standard medications. In 3 cases, olanzapine resolved vomiting completely and also improved anorexia, In 2 cases, vomiting was controlled for a limited period. No adverse effect was observed. These results suggest olanzapine is a useful agent for the management of both vomiting and anorexia.

[The opioid combination of transdermal fentanyl and sustained release morphine for refractory cancer pain--a case report].

Transdermal fentanyl (TDF) has been increasingly administered for the management of cancer pain. Occasionally, some patients fail to obtain poor analgesic effects with its dose escalation. We discuss a case of a 44-year-old male diagnosed with lung cancer with back pain caused by bone metastasis. He was administered a TDF of 75 microg/hr with good pain relief on admission. With time, the dose escalation to 300 microg/hr induced neuroexcitatory adverse effects without pain improvement. The conversion to 150 microg/hr TDF and sustained-release oral morphine 360 mg/day provided effective pain control. This clinical phenomenon demonstrated a possible association with the development of opioid tolerance. Although several experimental approaches regarding partial opioid substitution or combining different opioids for better pain control were suggested, the basic studies of opioid tolerance do not justify conclusions. In this case, partial opioid rotation and opioid combination were beneficial approaches to pain management.

[A possibility of the prognosis factor of serum cross-linked carboxyterminal telopeptide region of type I collagen (ICTP) as a marker of bone metastasis].

We measured ICTP in 126 patients suffering from cancer in our palliative care unit to investigate the clinical significance of serum cross-linked carboxyterminal telopeptide region of type I collagen (ICTP) and divided them into 2 groups according to the absence or presence of bone metastasis. 1) There was a relationship that of ICTP = -22.6Loge (Ccr) + 111.4 (r = 0.63, p < 0.01) between ICTP and creatinine clearance (Ccr) in non-metastasis group. The ICTP increased as renal function deteriorated. 2) In cancer patients with normal renal function of 40 ml/min/1.73 m2, ICTP was significantly higher in the group of metastasis than non-metastasis group. 3) In cancer patients who died, ICTP was high in both metastasis and non-metastasis groups and no difference was found between 2 groups. Duration of disease was significantly short in non-metastasis group than in metastasis group. These results suggest that ICTP is one of markers of bone metastasis, but higher value of ICTP is influenced by various factors such as renal function and may reflect the prognosis.