Immediate-release Oral Morphine Research Articles

Comparison of the Quality of Life of Cancer Patients with Pain Treated with Oral Controlled-Release Morphine and Oxycodone and Transdermal Buprenorphine and Fentanyl.

To compare the effects of oral morphine and oxycodone and transdermal fentanyl and buprenorphine on quality of life (QoL) of cancer patients with severe pain. Cancer patients with severe pain (NRS 6-10) treated at home and in outpatient clinics who failed to respond to non-opioids and/or "weak" opioids were randomized to morphine, oxycodone, fentanyl, or buprenorphine treatment for 28 days. Immediate-release oral morphine was rescued analgesic and 10-ml lactulose twice daily was prophylaxis of constipation; no antiemetics were used for prophylaxis. Above all, 62 patients participated and 53 patients completed the study. Good analgesia was obtained with all 4 opioids. Morphine was associated with the less negative impact of pain on the ability to walk and normal work, and tendency on activity (BPI-SF) and lower consumption of rescue morphine. All 4 opioids elicited similar adverse effects. According to ESAS, the intensity of nausea and drowsiness increased at the beginning but decreased as treatment continued. Appetite, well-being, anxiety, depression, and fatigue improved. No changes were seen in constipation, vomiting and dyspnea. Constipation was rarely observed with all opioids (BFI). Any opioids improved overall QoL and emotional functioning with tendency improving physical functioning (EORTC QLQ-C15-PAL). Activity improved (Karnofsky). Morphine induced greater improvement in physical functioning and trend in improvement mood (HADS). All opioids significantly improved patients' QoL. Morphine induced less negative impact of pain on daily activities and greater improvement in physical functioning with trends of better mood and less intense fatigue.

Effect of morphine on breathlessness and exercise endurance in advanced COPD: arandomised crossover trial.

The objective of the present study was to evaluate the effect of morphine on exertional breathlessness and exercise endurance in advanced chronic obstructive pulmonary disease (COPD).In a randomised crossover trial, we compared the acute effect of immediate-release oral morphine versus placebo on physiological and perceptual responses during constant-load cardiopulmonary cycle exercise testing (CPET) in 20 adults with advanced COPD and chronic breathlessness syndrome.Compared with placebo, morphine reduced exertional breathlessness at isotime by 1.2±0.4 Borg units and increased exercise endurance time by 2.5±0.9 min (both p≤0.014). During exercise at isotime, morphine decreased ventilation by 1.3±0.5 L·min-1 and breathing frequency by 2.0±0.9 breaths·min-1 (both p≤0.041). Compared with placebo, morphine decreased exertional breathlessness at isotime by ≥1 Borg unit in 11 participants (responders) and by <1 Borg unit in nine participants (non-responders). Baseline participant characteristics, including pulmonary function and cardiorespiratory fitness, were similar between responders and non-responders. A higher percentage of responders versus non-responders stopped incremental CPET due to intolerable breathlessness: 82 versus 33% (p=0.028).Immediate-release oral morphine improved exertional breathlessness and exercise endurance in some, but not all, adults with advanced COPD. The locus of symptom-limitation on laboratory-based CPET may help to identify patients most likely to benefit from morphine.

The Contribution of the International Pain Policy Fellowship in Improving Opioid Availability in Georgia

In the Republic of Georgia, the incidence and prevalence of cancer are increasing, signifying a growing need for palliative care and pain relief, including with controlled opioid medicines. As a signatory to the Single Convention, the Georgian government has a responsibility to ensure the adequate availability of controlled medicines for medical purposes; however, the consumption of morphine is very low, suggesting a high occurrence of unrelieved pain. In Georgia, palliative care development began in the 2000s including the adoption of a policy document in 2005, the creation of the National Palliative Care Coordinator in 2006, and important changes in Georgian legislation in 2007 and 2008, which served to lay a foundation for improving opioid availability. In 2008, a neurologist from the Sarajishvili Institute of Neurology and Neurosurgery in Tbilisi, and member of the Georgia National Association for Palliative Care, was selected to be an International Pain Policy Fellow to focus on improving opioid availability. Working with colleagues, government officials, and international experts, the Fellow contributed to several improvements to opioid availability, such as 1) positive changes to opioid prescribing legislation, 2) clarification of legislative terminology regarding dependence syndrome, 3) initiating the importation of both sustained-release and immediate-release oral morphine, and 4) improvements in the availability of sustained-release morphine. Despite these varied achievements, morphine consumption remains low in Georgia relative to the estimated amounts needed. The Fellow is continuing to study and understand the barriers that are impeding physician's prescription of opioids and patient's acceptance of them.

The effect of morbid obesity on morphine glucuronidation

The purpose of the present work was to study the change in morphine metabolic ratio in obese subjects before and after Roux-en-Y Gastric Bypass (RYGB) and to identify clinical and/or biological factors associated with this change. The pharmacokinetics (PK) of oral morphine (30mg), morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) was performed in patients before (n=25; mean BMI=43.2 (35.4–61.9)kg/m2), 7–15days (n=16) and 6 months after RYGB (n=19; mean BMI=32.3 (25.4–46.0)kg/m2). Morphine Cmax and AUC0-inf were significantly increased and morphine Tmax significantly shortened at 6 months after RYGB compared with preoperative data, indicating an important increase in the rate and extent of morphine absorption. The morphine metabolic ratio 0-inf M3G+M6G/Morphine, decreased significantly from the preoperative to 6 months postoperative period with an average of −26% (range −74%; +21%; p=0.004), but not in the immediate post-operative period. The change in morphine metabolic ratio was associated with a change in BMI, fat mass in kg, and triglyceride levels (rho=0.5, p≤0.04). The degree of change in several markers of low-grade inflammation, or the level of liver steatosis and fibrosis before surgery, was not associated with the change in morphine metabolic ratios. Our findings indicate that RYGB-induced weight loss significantly decreases morphine metabolic ratio, arguing for an effect of morbid obesity on glucuronidation. With glucuronide exposure at 6 months similar to preoperative values, a higher morphine AUC0-inf should encourage reducing morphine dosage in patients undergoing RYGB and chronically receiving immediate-release oral morphine.

A Multifaceted Approach to Improve the Availability and Accessibility of Opioids for the Treatment of Cancer Pain in Serbia: Results From the International Pain Policy Fellowship (2006–2012) and Recommendations for Action

Cancer is the second leading cause of death in Serbia, and at least 14,000–16,000 patients experience moderate-to-severe cancer pain every year. Cancer pain relief has been impeded by inadequate availability of opioid analgesics and barriers to their accessibility. In 2006, a Serbian oncologist was selected as an International Pain Policy Fellow. The fellow identified barriers to opioid availability in Serbia and implemented an action plan to address the unavailability of oral morphine, attitudinal and knowledge barriers about opioids, and barriers in the national opioid control policy, in collaboration with the government, local partners, and international experts, including those from the World Health Organization. Collaborative efforts resulted in availability of immediate-release oral morphine, registration of controlled-release hydromorphone, and reimbursement of oral methadone for cancer pain; numerous educational activities aimed at changing inadequate knowledge and negative attitudes toward opioids; recognition of opioids as essential medicines for palliative care in a new National Palliative Care Strategy; and recognition of the medical use of opioids as psychoactive-controlled substances for the relief of pain included in a new national law on psychoactive-controlled substances, and the development of recommendations for updating regulations on prescribing and dispensing opioids. An increase in opioid consumption at the institutional and national levels also was observed. This article outlines a multifaceted approach to improving access to strong opioids for cancer pain management and palliative care in a middle-income country and offers a potential road map to success.

A 44-Year-Old Woman With Excessive Sleepiness

A 44-year-old woman was referred by her primary care physician for a polysomnogram for further workup of excessive daytime sleepiness. She reported a 6-month history of uncontrollably falling asleep. She frequently dozed off while watching television, sitting inactive in public places, and talking to people. She had dozed off while driving, but had not had any driving accidents. Her Epworth Sleepiness Scale score was 21 of 24. She admitted to snoring, but no apneas were witnessed by her bed partner. She denied symptoms of morning headaches, gasping for air, leg jerking during sleep, cataplexy, sleep paralysis, hypnagogic hallucinations, gastroesophageal reflux during sleep, or insomnia. She usually went to bed at 10:00pmand woke up at 9:00am. She reported three to four nocturnal awakenings per night. She denied taking naps. Medical history included chronic pain from cervical spinal stenosis, hypothyroidism, hyperlipidemia, depression, restless legs, migraines, and gastroesophageal reflux disease. She had no known cardiac illnesses. Medications included levothyroxine, 50 μg daily; duloxetine, 60 mg daily; cyclobenzaprine, 10 mg tid; omeprazole, 20 mg daily; trazodone, 50 mg daily; gabapentin, 600 mg daily; tolterodine, 2 mg bid; cetirizine, 10 mg daily; extended-release oral morphine sulfate, 15 mg bid; and immediate-release oral morphine sulfate, 15 mg qid as needed for pain.

Palliative Care and Essential Drug Availability: Thailand National Survey 2012

Palliative care in Thailand was not well established in the past, but it is better supported by many organizations at present. Despite the change in the situation, the availability of essential drugs for palliative care has not been well studied. Our aim was to update the medical community on the current situation of essential drug availability for palliative care in Thai hospitals. The International Association for Hospice and Palliative Care (IAHPC) list of 34 essential drugs for palliative care was used in this survey. Five hundred and fifty-five hospitals replied to the questionnaire (response rate 57%). Eleven of the 24 nonopioid drugs were available above 90% in all hospitals. However, nonopioid drugs generally were less available in community hospitals (CH) and general hospitals (GH) than in large hospitals (LH). Tramadol was the most available weak opioid. Injectable morphine was the most available form of strong opioid in Thailand (96.9%). For the overall picture of oral morphine, immediate-release morphine was a less available form than the controlled-release form (32.2% versus 51.0%). Controlled-release oral morphine had a nearly two-fold better availability than immediate-release oral morphine in CH, GH, and LH, that is, cancer centers (CC), medical school hospitals (MH), regional hospitals (RH), and other government hospitals. In contrast, in private hospitals (PH), there was no difference between the availability of the controlled-release form and the immediate-release form. Transdermal fentanyl and methadone were also less available in Thailand (14.6% versus 16.5%, respectively). LH and PH have better overall nonopioid and opioid medication availability than CH and GH.

A Comparison of Change in the 0–10 Numeric Rating Scale to a Pain Relief Scale and Global Medication Performance Scale in a Short-term Clinical Trial of Breakthrough Pain Intensity

Pain intensity is commonly reported using a 0-10 Numeric Rating Scale in pain clinical trials. Analysis of the change on the Pain Intensity Numerical Rating Scale as a proportion has most consistently correlated with clinically important differences reported on the patient's global impression of change. The correlation of data from patients with breakthrough pain with a Pain Relief Scale and a different global outcome measures will extend our understanding of these measures. Data were obtained from the open titration phase of a multiple crossover, randomized, double-blind clinical trial comparing oral transmucosal fentanyl citrate with immediate-release oral morphine sulfate for the treatment of cancer-related breakthrough pain. Raw and percentage changes in the pain intensity scores from 1,307 episodes of pain in 134 oral transmucosal fentanyl citrate-naïve patients were correlated with the clinically relevant secondary outcomes of Pain Relief Verbal Response Scale and the global medication performance scale. The changes in raw and percentage change were assessed over time and compared with the ordinal Pain Relief Verbal Response Scale and Global Medication Performance Scale. The P value of the interaction between the raw pain intensity difference was significant (P = 0.034) for four 15-min time periods but not for the percentage pain intensity difference score (P = 0.26). We found similar results in comparison with the ordinal Pain Relief Verbal Response Scale (P = 0.0048 and P = 0.36 respectively) and global medication performance categories (P = 0.048 and P = 0.45, respectively). The change in pain intensity in breakthrough pain was more consistent over time and when compared with both the Pain Relief Verbal Response Scale and the Global Medication Performance Scale when the percentage change is used rather than raw pain intensity difference.

Pharmacokinetics of an immediate and extended release oral morphine formulation utilizing the spheroidal oral drug absorption system in dogs

This study investigated the pharmacokinetics of a human-labeled oral morphine formulation consisting of both immediate and extended release components in dogs. In a randomized design, 14 dogs were administered either 1 or 2 mg/kg morphine orally. Blood samples were collected up to 24 h post drug administration. Plasma concentrations of morphine were measured using high-pressure liquid chromatography with electrochemical coulometric detection. For both groups, maximal concentration occurred at 3 h post drug administration followed by a gradual decrease in morphine concentration over 24 h. There was substantial variability in morphine concentrations among dogs. The higher dose group produced a greater exposure (higher area-under-the-curve), higher peak concentration, longer half-life and a shorter time to peak concentration (t(max)). The specific oral morphine formulation used in this study produced sustained plasma morphine concentrations over 24 h compared with previous intravenous dosing and immediate-release oral morphine studies. However, the low morphine plasma concentrations and high variability produced from this formulation, suggest that the clinical application of this formulation at the doses evaluated in this study are limited.

A Double-Blind, Randomized, Crossover Comparison Between Single-Dose and Double-Dose Immediate-Release Oral Morphine at Bedtime in Cancer Patients

The European Association for Palliative Care guidelines for treatment of cancer pain recommend a double dose (DD) of immediate-release morphine at bedtime instead of single doses (SD) repeated every four hours throughout the night. A previous open controlled study reported more side effects after DD than after SD. The present study was a randomized, double-blind, crossover study comparison of DD and SD of immediate-release morphine during the night, followed by an open pharmacokinetic study. The primary outcome was average pain intensity during the night, as measured on an 11-point numerical rating scale. Secondary outcomes were morning pain, number of rescue medications, adverse effects (nausea, xerostomia, tiredness, sleep quality, and number of awaking episodes) and patient preference. Morphine and metabolites were quantified by a validated liquid chromatography-tandem mass spectrometry method. Nineteen patients completed the clinical study; 13 participated in the pharmacokinetic follow up. Average pain during the night for DD vs. SD was close to statistical significance (mean 0.8 and 1.4, respectively, P = 0.058; mean [95% confidence interval] for the difference was 0.50 [0.02, 1.0]). A similar trend was observed for strongest night pain ( P = 0.069) and sleep quality ( P = 0.077). Only two patients required rescue morphine. Four patients had no treatment preference; nine and six favored DD and SD, respectively. DD patients displayed higher area under the curve for morphine and morphine-6-glucuronide during the first part of the night. Although DD tended to perform slightly better than SD, a difference in average pain during the night of 0.50 has little clinical significance, and the two procedures are, therefore, clinically equivalent. It is speculated whether the initial higher exposure to morphine-6-glucuronide may have clinical significance.

Four years trial in elderly people of appraisal and comparison by geriatric assessment instruments: Use of high potency opioids for cancer pain control and quality of life

18610 Background: Pain is probably under-recognized and under-treated in the Elderly with advanced cancer disease but the effect of a therapy with high potency opioids is not studied so much in geriatric age people. To evaluate efficacy and tollerability of escalating doses of Transdermal Fentanyl (TTS-F) or equipollent doses of oral morphine long acting with Immediate Release Oral Morphine (IROM) as rescue medication for treatment of moderate-severe cancer pain, we have started a Multicentric Observational Analysis in four cancer centres of north-western Italy. Studies of oncological palliation using valid measures of quality of life show that patients may be willing to accept some side effects of treatment as long as they gain relief from tumor-related symptoms Methods: -TIQ (Therapy Impact Questionnaire) -VAS (Visual Analogic Scale): 0 to 10 -Toxicity (WHO criteria) -Geriatric Assessment for pts aged &gt;70 yrs (only at time 0): CIRS (Comorbility Index) IADL/ADL (Instrumental Activities Daily Living/Activities Daily Living). Patients characteristics -159 pts -Total Median Age: 66 yrs (range 38–86) -Median ECOG PS: 1 (range 0–2) -Elderly (&gt;70 yrs): 75. Pain Starting situation -Median starting VAS: 5.5 (range 3–9) -TIQ: depression 70 pts, cachexia 55 pts, dispnoea 40 pts -CIRS (Comorbidity index): comorbidity were present among 66 pts. TTS-Fentanyl starting dose: 25 mcg/h every 72 h (range 25–50 mcg) or oral morphine long acting 60–90 mg plus IROM 10 mg every 4–6 hours for breakthrough pain present in 38 pts Results: -Quickly pain VAS downloading during first two weeks of treatment (median VAS 1) -Analgesic doses were not significantly increased after two months and not exceeded WHO grade 2 -IROM rescue was similar to that observed for the overall population -TIQ, ADL and IADL were not influenced by therapy. Conclusions: High potency opioids (TTS-F or long acting morphine equipollent doses, plus Rescue-IROM) offers durable long term maintenance pain relief wild acceptable toxicity also in elderly people, is particularly useful for cancer pts with compliance problems and may be considered as first-line treatment for moderate/severe cancer pain. No significant financial relationships to disclose.

Italian observational trial of appraisal and comparison by geriatric assessment instruments. Use of high potency opioids for cancer pain control and quality of life in elderly people

8164 Background: Pain is probably under-recognized and under-treated in the Elderly with advanced cancer disease but, the effect of a therapy with high potency opioids is not studied so much in geriatric age people.To evaluate efficacy and tollerability of escalating doses of Transdermal Fentanyl (TTS-F) with Immediate Release Oral Morphine (IROM) as rescue medication,for treatment of moderate-severe cancer pain we have started a Multicentric Observational Analysis in four cancer centres of north-western Italy.Studies of oncological palliation using valid measures of quality of life,show that patients may be willing to accept some side effects of treatment, as long as they gain relief from tumor-related symptoms. Methods: -TIQ (Therapy Impact Questionnaire) -VAS (Visual Analogic Scale): 0 to 10 -Toxicity (WHO criteria) -Geriatric Assessment for pts aged>70 yrs (only at time 0): CIRS (Comorbility Index) IADL/ADL (Instrumental Activities Daily Living/Activities Daily Living) Patients characteristics -149 pts -Total Median Age: 66 yrs (range 38–86) -Median ECOG PS: 1 (range 0–2) -Elderly (>70 yrs): 65 Pain Starting situation -Median starting VAS: 5.5 (range 3–9) -TIQ: depression 68 pts, cachexia 50 pts, dispnoea 37 pts -CIRS (Comorbidity index): comorbidity were present among 56 pts. TTS-Fentanyl starting dose:25 mcg/h every 72 h (range 25–50 mcg) plus IROM 10 mg every 4–6 hours for breakthrough pain present in 38 pts Results: -Quickly pain VAS downloading during first two weeks of treatment (median VAS 1) -Analgesic doses were not significantly increased after two months and not exceeded WHO grade 2 -IROM rescue was similar to that observed for the overall population -TIQ, ADL and IADL were not influenced by therapy Conclusions: TTS-F plus Rescue-IROM offers durable long term maintenance pain relief wild acceptable toxicity also in elderly people, is particularly useful for cancer pts with compliance problems and may be considered as first-line treatment for moderate/severe cancer pain. The results on pts. QoL and the positive test of collaboration in Italian Regions are encouraging and justify a territorial planning of this program. No significant financial relationships to disclose.

Oral morphine and respiratory function amongst hospice inpatients with advanced cancer.

Respiratory depression is the opioid adverse effect feared most by physicians. This may hinder adequate dosing in cancer pain. The study was conducted to examine the respiratory function of patients with advanced cancer receiving significant doses (>100 mg/24 h) of oral morphine. Consecutive pain-free hospice inpatients with advanced cancer receiving high-dose immediate-release oral morphine were evaluated. A single assessment of respiratory rate (RR), arterial blood gas (ABG), and peak flow rate (PFR) was made at assumed morphine steady state. Venous blood was drawn for a trough morphine plasma level. Of 31 patients who consented to examination, 20 completed the study assessment; 12 had chronic bronchitis. The median morphine dose was 30 mg 4-hourly (range 20 to 90 mg). Only one patient had evidence of ventilatory impairment. Morphine does not commonly cause chronic ventilatory impairment when given in this way in this population even in the presence of pre-existing or concurrent respiratory disease. Oral morphine given repeatedly in individualized dosage is a safe and efficacious analgesic in the majority of those with advanced cancer.

Use of TTS Fentanyl as a Single Opioid for Cancer Pain Relief: A Safety and Efficacy Clinical Trial in Patients Naive to Mild or Strong Opioids

Background: Up to now, a transdermal therapeutic system (TTS) of fentanyl has been applied to cancer patients on opioid analgesics previously treated with mild opioids or morphine. The aim of this study was to investigate the efficacy and safety of TTS fentanyl (patch) administration as an analgesic to patients treated with opioid analgesics for moderate-to-severe cancer pain, with immediate-release oral morphine only as rescue medication. The prior analgesic medication of the patients did not include mild or strong opioids. Methods: The study group consisted of 113 patients (54 men and 59 women; age range: 21–87 years, mean ± SD 61.3 ± 14.84 years) with undertreated chronic cancer pain. The study period was 42 days. The patients were hospitalized for the first 3 days of the study; thereafter they were transferred to their home for the rest of the study. Daily cards were completed, noting their pain score (0–10 VAS), nausea, vomiting, constipation, skin reactions, dizziness or any other complaints. Vital signs were also recorded. Data assessments were made at baseline, on days 1, 2 and 3 (during hospitalization) and thereafter on days 7, 14, 21, 28, 35, and 42 after hospital discharge. The initial TTS fentanyl delivery rate was chosen depending on the patient’s analgesic requirements. All patients were given an oral morphine solution (5–10 mg), every 4–6 h, for the first 12 h, as rescue medication. Results: Baseline pain score was between 6 and 10 (mean ± SD 7.1 ± 1.7). The initial TTS fentanyl delivery rate was between 25 and 50 µg/h (mean ± SD 36.5 ± 15.7). On day 3, 95 patients (84%) reported a pain score ≤3 (mean ± SD 0.5 ± 0.8), 14 patients (12.4%) a pain score of 4 and 4 patients (3.5%) of 5–8. No adverse effects suggesting the discontinuation of the study were reported. From day 7 until the completion of the study, the mean pain score was between 1.3 and 0.16 while the TTS fentanyl delivery rate on day 42 was between 25 and 400 µg/h (mean ± SD 122.1 ± 81.2 µg/h). Conclusion: Analgesic treatment with TTS fentanyl used as a single opioid is effective and safe for cancer pain relief, given that is cautiously applied, in patients requiring strong opioid analgesics even if they were naive to strong or mild opioids.

Transdermal Fentanyl in Opioid-Naive Cancer Pain Patients: An Open Trial Using Transdermal Fentanyl for the Treatment of Chronic Cancer Pain in Opioid-Naive Patients and a Group Using Codeine

To treat cancer pain, physicians often decide to jump directly from step 1 of the World Health Organization (WHO) analgesic ladder to step 3. The use of transdermal fentanyl in patients with cancer pain who had either used no opioid before, or only codeine, is evaluated in the present trial. Both opioid-naive ( N = 14) and codeine-using ( N = 14) patients started with transdermal fentanyl in the lowest available delivery rate (25 μg/hr). Immediate-release oral morphine was present as “rescue” medication. Transdermal fentanyl provided good to excellent pain relief in the majority (68 %) of these patients. During the study, 5 patients continued with 25 μg/hr, and the others used a higher dose. Clinically relevant respiratory depression was not observed. The common side effects of opioids were found; constipation was mentioned by 3 patients (11 %). Transdermal fentanyl appeared a safe analgesic in these opioid-naive cancer pain patients. In this study, WHO step 2 could be skipped without untoward complications.

A study of controlled-release oral morphine (Ms Contin) in an advanced cancer hospital

Abstract An oral controlled-release morphine sulfate tablet (MS Contin) was evaluated for efficacy and safety in advanced cancer patients with significant pain. Results supported the safety and efficacy of every-12-hours dosing with this drug. The mean daily morphine requirements of these patients was large (444.7 ± 96.7 mg) but not significantly greater than that required when treated with immediate-release oral morphine sulfate dosed every four hours. The global impression of patients and investigators was that this sustained-release sulfate preparation was better regarding analgesia and side effects relative to immediate release oral morphine and other prior analgesics.