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With the objective of comparing incidence of adverse events of the opioids codeine, hydrocodone, and tramadol in the relief of cancer pain, we conducted a randomized controlled trial in which patients with cancer were randomly assigned according to a computer-generated schedule to receive one of the three opioids. Of the 177 patients who participated, 62 patients received hydrocodone, 59 patients received codeine, and 56 patients received tramadol. The pain experienced by the participants originated most frequently from the stomach, breast, or prostate gland and was classified as either somatic (33%), visceral (52%), mixed (6%), or neuropathic (9%). At the first visit, 60% of the patients described their pain intensity as moderate (4-6/10), with the remaining 40% of the patients describing their pain as severe (7-10/10). The symptoms most associated with pain were weakness, insomnia. and anorexia. In 77% of the total number of cases, the patient was aware of his/her diagnosis prior to admittance to the palliative care unit. Of the total number of cases, 57% fell in the age range of 60-89 years old and 50% of the participants were female. No significant statistical difference in the analgesic efficacy of the three opioids was found (p: 0.69; chi(2): 0.73). Use of tramadol produced higher rates of adverse events than codeine and hydrocodone: vomiting, dizziness, loss of appetite, and weakness (p < 0.05).
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PMID:Incidence of weak opioids adverse events in the management of cancer pain: a double-blind comparative trial. 1729 54

Oxycodone is a semi-synthetic opioid with an agonist activity on mu, kappa and delta receptors. Equivalence with regard to morphine is 1:2. Its effect commences one hour after administration and lasts for 12 h in the controlled-release formulation. Plasma halflife is 3-5 h (half that of morphine) and stable plasma levels are reached within 24 h (2-7 days for morphine). Oral bioavailability ranges from 60 to 87%, and plasma protein binding is 45%. Most of the drug is metabolised in the liver, while the rest is excreted by the kidney along with its metabolites. The two main metabolites are oxymorphone--which is also a very potent analgesic--and noroxycodone, a weak analgesic. Oxycodone metabolism is more predictable than that of morphine, and therefore titration is easier. Oxycodone has the same mechanism of action as other opioids: binding to a receptor, inhibition of adenylyl-cyclase and hyperpolarisation of neurons, and decreased excitability. These mechanisms also play a part in the onset of dependence and tolerance. The clinical efficacy of oxycodone is similar to that of morphine, with a ratio of 1/1.5-2 for the treatment of cancer pain. Long-term administration may be associated with less toxicity in comparison with morphine. In the future, both opioids could be used simultaneously at low doses to reduce toxicity. It does not appear that there are any differences between immediate and slow-release oxycodone, except their half-life is 3-4 h, and 12 h, respectively. In Spain, controlled-release oxycodone (OxyContin) is marketed as 10-, 20-, 40- or 80-mg tablets for b.i.d. administration. Tablets must be taken whole and must not be broken, chewed or crushed. There is no food interference. The initial dose is 10 mg b.i.d. for new treatments and no dose reduction is needed in the elderly or in cases of moderate hepatic or renal failure. Immediate-release oxycodone (OxyNorm) is also available in capsules and oral solution. Side effects are those common to opioids: mainly nausea, constipation and drowsiness. Vomiting, pruritus and dizziness are less common. The intensity of these side effects tends to decrease over the course of time. Oxycodone causes somewhat less nausea, hallucinations and pruritus than morphine.
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PMID:Oxycodone: a pharmacological and clinical review. 1752 40

Fentanyl buccal tablet (FBT) is a new opioid formulation providing rapid-onset analgesia for the treatment of breakthrough pain (BTP). This study evaluated FBT for BTP in opioid-tolerant patients with chronic cancer pain. The study had a randomized, double-blind, placebo-controlled design and was conducted at 30 outpatient treatment centers in the United States. Following open-label titration, patients were randomly assigned to 1 of 18 double-blind dose sequences (7 FBT tablets, 3 placebo) to treat 10 BTP episodes. Pain intensity was measured on an 11-point scale (0 = no pain; 10 = worst pain). The primary efficacy measure was the sum of pain intensity differences (PIDs) for the first 60 minutes (SPID60); secondary efficacy measures included PIDs and pain relief (PR) measured from 5 minutes through 2 hours. Adverse events (AEs) were recorded. Of 129 patients enrolled, 87 entered the double-blind phase. SPID60 significantly favored FBT versus placebo (mean +/- SE, 9.7 +/- 0.63 vs 4.9 +/- 0.50; P < 0.0001). Secondary measures also favored FBT: PIDs and PR showed significant differences versus placebo at 10 minutes (0.9 vs 0.5; 0.815 vs 0.606, respectively, P < 0.0001) and all subsequent time points (P < 0.0001). AEs were typical of opioids (eg, nausea, dizziness, fatigue). In conclusion, in this study of opioid-tolerant patients with chronic cancer pain and BTP, FBT was efficacious, well tolerated, demonstrated rapid onset of analgesia (within 10 minutes), and had a sustained effect.
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PMID:Fentanyl buccal tablet for relief of breakthrough pain in opioid-tolerant patients with cancer-related chronic pain. 1770 23

Ketamine used in conjunction with other analgesics has dissociative, analgesic, sedative, and amnesic properties. Ketamine potentiates opiates and analgesics, is rapid acting, and is relatively safe. The United Kingdom and United States use ketamine with opioids in adjuvant pain management for a variety of conditions, including cancer pain. Adults and children benefit from the analgesic effects of these medications, especially at the end of life when the reduction of severe cancer pain has refractory or dose-limiting effects. For adults, ketamine and opioids are administered by a patient-controlled analgesia pump. The medication combination has decreased use of opioids and increased activities of daily living. Nursing considerations include close monitoring of vital signs during the initial dosage and follow-up observations of the effectiveness of the medications. Vital signs are checked every four hours after the initial dosage along with evaluation of the effectiveness of the dosage and observation for signs of oxygenation of tissue. Patients have better mobility and quality of life when receiving ketamine as an adjuvant therapy, which promotes assistance with their nursing care. Side effects may occur from administering ketamine and include nausea, vomiting, dizziness, and emotional distress. Standard orders help alleviate problems with those symptoms.
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PMID:The use of ketamine as adjuvant therapy to control severe pain. 1856 30

Studies of populations with chronic cancer pain have shown a high prevalence of breakthrough pain (BTP), defined as transitory, severe flares of pain that occur on a background of otherwise controlled, persistent pain. High BTP prevalence rates have also been reported in patients with chronic noncancer pain, although data in these patient populations are more limited. The incidence of BTP appears to be associated with progression of chronic disease, with more than 80% of patients reporting BTP with far-advanced, end-stage cancer and noncancer terminal conditions (1). The most widely accepted therapeutic approach for the management of BTP involves use of short-acting opioids taken as needed in addition to the around-the-clock opioid regimen being used for the continuous component of the persistent pain syndrome. For some patients, an optimal treatment outcome for BTP may be unattainable because of a mismatch between the time course of the BTP episode and the onset of analgesia of short-acting opioids. Breakthrough pain typically reaches peak intensity within a few minutes, whereas the onset of analgesia with traditional, orally administered short-acting opioids is between 30 and 60 minutes (2-7). Consequently, treatment outcomes for BTP are likely to be improved with agents that have a more rapid onset of analgesia. Fentanyl buccal tablet (FBT) is a new formulation of fentanyl indicated for the management of BTP in patients with cancer who are already receiving, and who are tolerant to, opioid therapy for their underlying persistent cancer pain. The FBT formulation uses OraVescent (Cephalon, Inc., Frazer, PA, USA) drug delivery technology to provide rapid absorption of fentanyl through the buccal mucosa. In pharmacokinetic studies in healthy volunteers, FBT demonstrated high, early systemic absorption. In addition, FBT delivered a larger proportion of the fentanyl dose transmucosally and produced a greater early systemic exposure than oral transmucosal fentanyl citrate (OTFC), which is also indicated for the management of BTP in opioid-tolerant cancer patients. A number of short-term studies have evaluated the efficacy, safety and tolerability of FBT in the management of BTP in opioid-tolerant patients with chronic pain. All these studies included an open-label dose-titration phase prior to randomized, placebo-controlled, double-blind treatment. Pain Intensity of a BTP episode was measured using an 11-point scale (0 = no pain, 10 = worst pain), and the primary outcome measure was the Summed Pain Intensity Difference (SPID) at a specified time point. Secondary efficacy measures included Pain Relief, Pain Intensity Differences, and the proportion of BTP episodes demonstrating >or=33% and >or=50% improvement in Pain Intensity scores at each time point postdose, and the proportion of BTP episodes requiring supplemental medication. In a pivotal study of opioid-tolerant patients with cancer-related chronic pain and BTP, the primary outcome measure, SPID at 30 minutes (SPID(30)), significantly favored FBT compared with placebo (mean +/- SE: 3.0 +/- 0.12 vs. 1.8 +/- 0.18, p<0.0001). Better efficacy was also observed with FBT compared with placebo for pain relief, Pain Intensity Differences, and the proportion of episodes showing >or=33% and >or=50% improvement in Pain Intensity Scores. Treatment with FBT was generally well tolerated. Most adverse events were mild to moderate in severity and typical of those associated with opioid use (e.g., nausea, dizziness) (8). Similar results have been observed in studies of opioid-tolerant patients with BTP in association with noncancer-related chronic pain. In a study of patients with chronic low back pain, the primary outcome measure, SPID(60), significantly favored FBT over placebo (mean +/- SE: 8.3 +/- 0.66 vs. 3.6 +/- 0.57, p <0.0001). All secondary efficacy measures were similarly improved, with Pain Intensity Differences and Pain Relief scores showing significant differences versus placebo as early as 10 and 15 minutes, respectively. As in the study of cancer patients, treatment with FBT was well tolerated (9). Across all studies, there was no simple linear relationship between the effective dose of FBT and the dose of the around-the-clock opioid regimen or the previous supplemental opioid, indicating that doses of FBT should be individually titrated to effectiveness rather than calculated as a percentage of existing opioid regimens. This monograph summarizes current data on the clinical pharmacology, efficacy, safety and tolerability of FBT relating to the management of opioid-tolerant patients with BTP in association with chronic pain.
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PMID:Fentanyl buccal tablet. 1830 3

Chronic pain requires chronic treatment. Dihydrocodeine retard (DHC) complies with the requirements for treatment of chronic pain: its sustained release formula provides pain relief for up to 12 h. Thus, taking two tablets of this preparation daily is sufficient to ensure continuous pain relief. Patients and methods The 309 physicians participating in the study treated a total of 1502 patients and provided more than 5000 reports containing data on pain relief and side effects. Treatment was performed according to the WHO principles for the analgesic treatment of cancer pain patients, i.e., doctors and patients were taught that two tablets are taken per day, one in the morning and one in the evening, irrespective of whether pain was present or not. Most of the data were derived from the first 4 weeks of treatment. Patients were selected at random. All had chronic pain, but the diagnosis was not a selection criterion. The patients had had prior treatment with various analgesic regimens, and in most cases drugs were administered at irregular intervals, i.e., on demand. About half of the patients (54%) suffered from pain related to the musculoskeletal system such as back pain, joint pain, polyarthritis. Twenty-four percent had cancer pain and 22% had pain caused by other sources, mostly neuropathic pain, including cases of severe postherpetic neuralgia. Most of the patients were older than 50 years; the average age in the patient population was 62 years. There were 816 women and 686 men. Patients assessment of analgesic treatment was performed before starting therapy with DHC (thus conferring to prior therapy) and after 1 and 2 weeks of treatment with the new drug. While only about 10% of the patients found their prior pain treatment excellent or good, nearly 80% rated the treatment with DHC as excellent or good and only 2% as bad.Severity of pain was assessed by the patients on a four-step verbal rating scale ranging from "no or little pain" to "extremely strong pain". At the time of admission to this post-marketing surveillance 51.5% of the patients suffered from very strong pain and 41% reported strong pain. Five percent had extremely strong pain and only 2.1% reported no or little pain. After 2 weeks of treatment with DHC, 54.5% had little or no pain, 29% suffered from strong pain, 7% from very strong, and 0.4% from extremely strong pain.Sleeping problems are known to be reported by patients with chronic pain. They often cannot sleep continuously for more than a few hours. Thus, the effect of DHC on sleep was evaluated. Before starting the new treatment only 8% of the patients were having uninterrupted sleep for 6 h or more, and more than 50% of the patients slept less than 3 h. During treatment with DHC 48% of the patients had more than 6 h of uninterrupted sleep and about 82% slept continuously for more than 3 h per night. Side effects About 20% of patients reported nausea at baseline (during previous treatment); vomiting was reported in 7.6%. These percentages did not change during the first week of treatment with sustained-release DHC and even decreased slowly during the next 3 weeks. The frequency of constipation increased from 14% at baseline to about 29.5% at the end of the second week of treatment with DHC with no change during the next four weeks. A total of 312 side effects were mentioned in 5308 reports delivered by the 1502 patients during the treatment with DHC (including multiple reports). The most frequent side effects were gastrointestinal (n=106), followed by symptoms related to the central nervous system such as dizziness, sedation, etc. (n=50), and non-specific symptoms such as indisposition (n=29). Other specific symptoms were rare and distributed over many different organ systems. Insummary, the findings of this post marketing surveillance study suggest that sustained-release dihydrocodeine is an effective and safe analgesic drug for the treatment of chronic pain of various causes.
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PMID:[Pain treatment with dihydrocodeine slow release. Results of a post marketing surveillance study.]. 1841 87

Morphine is the preferred strong opioid analgesic. Most of the adverse effects, such as daytime drowsiness, dizziness, mental clouding, and effects on cognitive and psychomotor function or nausea and vomiting, usually resolve with time. The main continuing adverse effect of morphine is constipation, and prophylactic use of laxative is almost always required. We are presenting retrospective data of 11 patients admitted in our palliative care unit over the past 5 months for new (not yet received any opioid analgesic in any form) and severe cancer pain management. It was found that none of the patients was having constipation with intravenous morphine. This finding can be explained on the basis of differences in pharmacologic profiles, in affinity to opioid receptor, and a higher exposure of opioid-binding receptor in the GI tract after oral administration of morphine compared with intravenous morphine. This explanation was further affirmed as constipation and need for laxative was reported by 7 of the 11 patients when they were given the equi-analgesic oral doses of morphine. Thus, the route of administration seems to be responsible for the above finding; hence, further evaluation with prospective observation and data collection is being planned to look for external validity in a larger population catered by our palliative care unit.
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PMID:Intravenous morphine can avoid distressing constipation associated with oral morphine: a retrospective analysis of our experience in 11 patients in the palliative care in-patient unit. 1953 98

(1) When oral morphine does not relieve severe pain and when there is no specific treatment for the underlying cause, the first option is to try subcutaneous or intravenous administration. If this standard treatment fails or is poorly tolerated, intrathecal injection is usually preferred as the direct route to the central nervous system. However, one-quarter to one-half of patients still do not achieve adequate pain relief, and adverse effects are relatively frequent; (2) Ziconotide is not an opiate and is not related to the usual classes of drugs that interfere with nervous transmission in the posterior horn of the spinal cord. Marketing authorization has been granted for "severe, chronic pain in patients who require intrathecal analgesia". The Summary of Product Characteristics (SPC) recommends continuous infusion via an intrathecal catheter connected to a pump; (3) Clinical evaluation of ziconotide does not include any trials versus morphine in patients with nociceptive pain, or any trials versus tricyclic or antiepileptic drugs in patients with neurogenic pain; (4) In a trial in 220 patients in whom systemic morphine had failed, the mean pain score on a 100-mm visual analogue scale was 69.8 mm after three weeks on ziconotide, compared to 75.8 mm with placebo. This difference, although statistically significant, is clinically irrelevant. The proportion of "responders" (reduction of at least 30% in the initial pain score) was respectively 16.1% and 12.0% (no statistically significant difference); (5) The two other placebo-controlled trials included 112 patients with pain linked to cancer or HIV infection, and 257 patients with non-cancer pain. After a titration phase lasting 5 to 6 days, a combined analysis of the two trials showed that the mean pain score was 48.8 mm with ziconotide and 68.4 mm with placebo (statistically significant difference). However, many patients did not complete the titration phase. Efficacy also appeared to differ according to the type of pain; ziconotide was more effective on cancer pain than on neurogenic pain; (6) The main adverse effects of ziconotide in clinical trials were cerebellovestibular disorders such as ataxia, dizziness, and gait disorders, as well as confusion, hallucinations (increased in cases of overdose), nausea, vomiting, postural hypotension, and urine retention. About 40% of patients had an elevation in muscle creatine kinase activity, through an unknown mechanism; (7) Intrathecal administration carries a risk of infection (especially meningitis). Some patients might experience a paradoxical increase in pain with ziconotide; (8) In practice, the efficacy of ziconotide in relieving neurogenic pain remains to be established. In cancer pain, the available evidence showing that ziconotide is effective after opiate failure is too weak in view of the potential risks. It is better to re-examine and, if possible, correct the reasons for opiate treatment failure rather than prescribe ziconotide.
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PMID:Ziconotide: new drug. Limited analgesic efficacy, too many adverse effects. 1953 Mar 73

BACKGROUND: Fentanyl buccal tablet (FBT; FENTORA(R), Cephalon, Inc., Frazer, PA, USA) is indicated in the US for breakthrough pain in patients with cancer who are already receiving and are tolerant to around-the-clock opioid therapy for underlying persistent cancer pain. For each individual patient, FBT should be titrated to the effective dose. OBJECTIVE: The primary objective was to characterize the pharmacokinetic parameters of FBT 400 microg administered as a single 400 microg tablet (regimen A) or as two 200 microg tablets given simultaneously (regimen B) and determine whether these are bioequivalent in healthy Japanese volunteers. Regimen C (two 200 microg tablets 30 minutes apart) was also compared as a secondary objective. METHODS: Healthy Japanese adults received regimens A, B, and C in a crossover fashion. Naltrexone was given to minimize the opioid effects of fentanyl. Serum fentanyl concentrations were determined in venous blood collected through 36 hours post dose. Regimens were declared bioequivalent with respect to bioavailability (as reflected by AUC(0-infinity), AUC(0-last), and C(max)) if the 90% confidence interval (CI) of the regimens' ratio fell within 0.80-1.25 (80%-125%). RESULTS: Twenty-nine volunteers (13 men, 16 women) were enrolled; 24 completed the study. Regimens A and B had bioequivalent systemic exposure parameters (B/A [90% CI]: AUC(0-infinity)108.4 [103.4, 113.7], AUC(0-last) 106.1 [100.7, 111.7], and C(max) 92.3 [83.2, 102.4]). Regimen C was bioequivalent to both A and B for AUCs, but only to B for C(max). Median time to C(max) was 45 minutes for regimen A and 60 minutes for regimens B and C. The most frequent AEs were dizziness, application-site erythema, headache, somnolence, nausea, and vomiting. All AEs were mild or moderate. CONCLUSIONS: Bioavailability of fentanyl after FBT 400 microg administered as a single tablet was bioequivalent to that after 2 simultaneously administered 200 microg tablets in healthy Japanese volunteers. AEs were mild or moderate.
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PMID:Relative Bioavailability of Fentanyl Following Various Dosing Regimens of Fentanyl Buccal Tablet in Healthy Japanese Volunteers. 1991 9

Fentanyl buccal tablet (FBT) is indicated for the treatment of breakthrough pain in patients who are already receiving, and who are tolerant to, opioid therapy for underlying, persistent cancer pain. Breakthrough pain may be severe or excruciating, and some patients may require high doses of rapid-onset opioids to obtain adequate analgesia. The objective of this study was to assess the dose proportionality of FBT over a range of 600-1300 microg in healthy subjects. This was a randomized, open-label, four-period, crossover, single-centre study of FBT (Fentora) conducted in healthy adult subjects who were not tolerant to opioids. The study included 120 men and women aged 18-45 years with a body mass index of 20-30 kg/m2 who had no clinically significant findings on medical and psychiatric histories, physical examination, ECG or standard clinical laboratory tests, and who had a negative urine screen for drugs and alcohol. Eligible subjects were randomized to one of four dose sequences: ABDC, BCAD, CDBA and DACB, where A, B, C and D were FBT doses from lowest to highest (600, 1000, 1200 and 1300 microg). Each dose of FBT was separated by a minimum of 7 days. Naltrexone 50 mg was administered to block the opioid receptor-mediated effects of fentanyl. Plasma fentanyl concentration was measured through 72 hours after placement of FBT. The main outcome measures, maximum plasma fentanyl concentration (C(max)) and area under the plasma drug concentration versus time curve from time zero to infinity (AUC(infinity)), were analysed to determine dose proportionality. Other pharmacokinetic parameters were also evaluated. Dose proportionality was concluded if the two-sided 90% confidence intervals (CIs) for the slopes of the C(max) versus dose and AUC(infinity) versus dose curves were completely contained within the range of 0.711-1.289. The safety and tolerability of FBT were assessed throughout the study. The slope for C(max) versus dose was 0.8627 (90% CI 0.7730, 0.9525), and the slope for AUC(infinity) versus dose was 0.9330 (90% CI 0.8738, 0.9922). Given that the CIs for C(max) and AUC(infinity) were within the predefined range of 0.711-1.289, dose proportionality was concluded over the 600-1300 microg range. The mean dose-normalized plasma fentanyl concentration reached 80% of C(max) within 25 minutes; plasma fentanyl concentration was maintained at this level for 3 hours after dose. No unexpected safety or tolerability concerns were noted in the naltrexone-blocked healthy subjects. Seventy-four subjects (68%) experienced adverse events (AEs); all were mild (56 [51%]) or moderate (18 [17%]). The most common AEs were nausea, dizziness and headache. No serious AEs were reported. The dose proportionality of FBT from 600-1300 microg was shown in healthy subjects. Based on the data, when FBT is titrated up to 1300 microg, a predictable and linear increase in systemic exposure can be expected. Currently, FBT is approved up to 800 microg. This study provides pharmacokinetic data to support a potential, expanded therapeutic dose range of FBT.
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PMID:Dose proportionality of fentanyl buccal tablet in doses ranging from 600 to 1300 microg in healthy adult subjects: a randomized, open-label, four-period, crossover, single-centre study. 2044 Dec 45


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