Immediate- or sustained-release morphine for dose finding during start of morphine to cancer patients: a randomized, double-blind trial. A controlled study of sustained-release morphine sulfate tablets in chronic pain from advanced cancer. Role of rectal route in treating cancer pain: a randomized crossover clinical trial of oral versus rectal morphine administration in opioid-naive cancer patients with pain. Medical therapy of malignant nerve pain. A randomised double-blind explanatory trial with naproxen versus slow-release morphine. Comparison of morphine slow release tablet (MST) and morphine sulphate solution (MSS) in the treatment of cancer pain. Placebo-blinded study of morphine sulfate sustained-release tablets and immediate-release morphine sulfate solution in outpatients with chronic pain due to advanced cancer. Pharmacokinetics and clinical efficacy of oral morphine solution and controlled-release morphine tablets in cancer patients. Controlled release morphine tablets: a double-blind trial in patients with advanced cancer. Randomized, double-blind, cross-over trial comparing safety and efficacy of oral controlled-release oxycodone with controlled-release morphine in patients with cancer pain. Efficacy, safety, and steady-state pharmacokinetics of once-a-day controlled-release morphine (MS Contin XL) in cancer pain. Control of severe pain with sustained-release morphine tablets v. oral morphine solution. Evaluation of a cancer pain model for the testing of long-acting analgesics. The effect of MS Contin in a double-blind, randomized crossover design. Effects of controlled-released morphine on quality of life for cancer pain. Dextropropoxyphene versus morphine in opioid-naive cancer patients with pain. Comparative efficacy and safety of controlled-release morphine suppositories and tablets in cancer pain. Comparison of sustained-release morphine with sustained-release oxycodone in advanced cancer patients. Transdermal fentanyl versus sustained-release oral morphine in cancer pain: preference, efficacy, and quality of life. The TTS-Fentanyl Comparative Trial Group. Morphine or oxycodone in cancer pain? Oral tramadol, a mu-opioid agonist and monoamine reuptake-blocker, and morphine for strong cancer-related pain. A randomized crossover study comparing the efficacy and tolerability of a novel once-daily morphine preparation (MXL capsules) with MST Continus tablets in cancer patients with severe pain. Pharmacokinetics and pharmacodynamics of twenty-four-hourly Kapanol compared to twelve-hourly MS Contin in the treatment of severe cancer pain. Comparison of a once-a-day sustained-release morphine formulation with standard oral morphine treatment for cancer pain. Opioid treatment for radiating cancer pain: oral administration vs. epidural techniques. Efficacy and pharmacokinetics of a new controlled-release morphine sulfate 200-mg tablet. Morphine at gramme doses: kinetics, dynamics and clinical need. Controlled-release oxycodone and morphine in cancer related pain. Pharmacokinetics and efficacy of rectal versus oral sustained-release morphine in cancer patients. Comparison of oral controlled-release morphine with transdermal fentanyl in terminal cancer pain. Oral controlled-release morphine sulfate. Analgesic efficacy and side effects of a 100-mg tablet in cancer pain patients. Clinical observations on controlled-release morphine in cancer pain. The evaluation of analgesic effects in cancer patients as exemplified by a double-blind, crossover study of immediate-release versus controlled-release morphine. A randomized study on oral administration of morphine and methadone in the treatment of cancer pain. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Controlled-release morphine in cancer pain. Is a loading dose required when the formulation is changed? Efficacy and tolerance of oral dipyrone versus oral morphine for cancer pain. Control of cancer-related pain with MS Contin: a comparison between 12-hourly and 8-hourly administration. [Morphine depot tablets compared with conventional morphine tablets in the treatment of cancer pain]. Controlled-release oxycodone compared with controlled-release morphine in the treatment of cancer pain: a randomized, double-blind, parallel-group study. The Brompton mixture versus morphine solution given orally: effects on pain. Morphine and oxycodone hydrochloride in the management of cancer pain. A comparative study of controlled-release morphine (CRM) suspension and CRM tablets in chronic cancer pain. Comparison of TTS-fentanyl with sustained-release oral morphine in the treatment of patients not using opioids for mild-to-moderate pain. Methadone versus morphine as a first-line strong opioid for cancer pain: a randomized, double-blind study.
A titration procedure using immediate-release morphine given 4-hourly is recommended during start of oral morphine for cancer pain. This recommendation is not based on evidence from controlled studies, and many physicians start morphine treatment with controlled-release morphine. We included 40 patients with malignant disease and pain despite treatment with opioids for mild to moderate pain in a randomized, double-blind, double-dummy, parallel-group study comparing titration with immediate-release morphine given 4-hourly with titration with sustained-release morphine given once daily. The primary end point was the time needed to achieve adequate pain relief Secondary end points were other symptoms (nausea, tiredness, lack of sleep, vertigo, appetite and constipation), health related quality of life and patient satisfaction. The mean times needed for titration were 2.1 (95% CI; 1.4-2.7) days using immediate-release morphine and 1.7 (95% CI; 1.1-2.3) days using sustained-release morphine. Patients titrated with immediate-release reported statistically significant more tiredness at the end of titration. We observed no other differences in adverse effects or health related quality of life functions between the two treatments. Similar global satisfactions with the morphine treatments were reported. In conclusion, a simplified titration using sustained-release morphine once daily is equally effective as immediate-release morphine given 4-hourly. The purpose of this double-blind crossover study was to determine whether a sustained-release morphine sulfate (SRMS) tablet given orally every 12 hours could adequately replace immediate-release morphine sulfate solution (IRMS) given orally every 4 hours in hospitalized patients with chronic pain from advanced cancer. Of 33 patients entered, 27 completed the study and were included in the efficacy and safety analysis. Patients were initially randomized to receive either 30-mg SRMS tablets every 12 hours or IRMS at the same mg/24 hours dose, every 4 hours. After 2 days, a crossover was performed, and patients received the alternate treatment for 3 days. Pain and side effects were assessed using a standard 100 mm visual analogue scale (VAS). There were no statistically significant differences between the two treatment groups for mean VAS pain scores or scores for sleepiness, nausea, depression, and anxiety. The incidence of breakthrough pain was similar for both treatment groups, as was the incidence of confusion and constipation. The results demonstrated that SRMS is a safe, effective analgesic preparation for patients who require oral opioids for cancer pain. The data also support the conclusion that sustained-release morphine tablets administered every 12 hours can replace an immediate-release morphine solution administered every 4 hours. The aim of this double-blind, double-dummy, crossover study was to compare the efficacy, tolerability, and time of onset of analgesia after the administration of 10 mg of morphine hydrochloride via the oral and rectal routes in opioid-naive cancer patients with pain.
                Thirty-four patients with cancer pain and no previous opioid treatment were randomized to receive morphine hydrochloride 10 mg orally or rectally (in the form of a microenema) for 2 days. During days 3 and 4, a crossover took place. The scores of pain, nausea, and sedation (visual analog scale of 0 to 100) calculated as the percentage change from baseline (before opioid administration) were assessed at different intervals up to 240 minutes. The number of vomiting episodes was recorded. Parity tests and analysis of variance (ANOVA) were performed to compare the two administration routes.
                A significant difference in pain intensity was achieved 10 minutes after rectal administration compared with 60 minutes after oral administration. There was still a significant reduction in pain via the rectal route after 180 minutes versus via the oral route after 120 minutes. No significant difference was observed in the intensity of sedation, nausea, or number of vomiting episodes between the oral and rectal routes.
                A liquid solution of morphine is well absorbed via the rectal route. Rectal morphine is safe, effective, easy to manage, and inexpensive, with a rapid onset of action. Rectal morphine can be considered a valid alternative route for opioid administration and may also be used when rescue doses of morphine are required in patients regularly treated with oral or parenteral opioids. It is uncertain whether there exists a nociceptive component in malignant nerve pain responsive to NSAIDs and opioids. 20 patients with malignant nerve pain were randomly assigned to treatment with naproxen 1500 mg versus slow-release morphine 60 mg daily during 1 week, followed by cross-over medication during the second week in a double-blind, double-dummy protocol. In the 16 evaluable patients, a significant (P < 0.05) reduction of 26% (S.E. +/- 7.9) in pain intensity was reached at day 7, compared to baseline pain. At day 7, significant pain relief of 32% (P < 0.05) was observed in the naproxen group, but not in the morphine group (21%, P = 0.14). Patients using morphine needed approximately twice as much paracetamol rescue than patients using naproxen. Additional pain relief could be observed in 4/9 patients with cross-over medication. These data support the concept of a nociceptive component in malignant nerve pain responding to NSAIDs and opioids, and favour the combination of both an anti-inflammatory drug and an opioid for symptomatic pain relief. A cross-over, single blind trial of MST and MSS in relieving pain of advanced cancer patients is described. Forty-nine cases completed the study. Both MST and MSS gave equally excellent pain relief in the patients as judged by the pain score of VAS and pain rating scale by a nurse, and the duration of sleep. The daily effective dose was 55.5 +/- 19.7 mg for MST and 61.0 +/- 11.0 mg of MSS. This study was conducted to compare the relative analgesic efficacy and safety of an every-4-hour immediate-release oral morphine (IRM) solution with that of an every-12-hour sustained-release oral morphine (SRM) formulation.
                This was a double-blind, placebo-blinded, crossover study in 34 adult male and female outpatients with pain due to advanced cancer. Baseline data were collected on day 1. On days 2 and 3, randomly assigned patients received either placebo plus IRM (Roxanol; Roxane Laboratories, Inc, Columbus, OH; 20 mg/mL) at 2, 6, and 10 am, and 2, 6, and 10 pm, or alternatively SRM (Oramorph SR; Roxane Laboratories, Inc; 30 mg) at 10 AM and 10 PM. Patients were then crossed over to the alternate treatment for days 4 through 6. Pain relief was measured using a conventional 100-mm visual analog scale (VAS) and by recording the incidence of breakthrough pain. Information on side effects was obtained from VAS scores for sedation, nausea, anxiety, and depression; by directly questioning the patient as to mental confusion, bowel movements, and laxative use; and from Karnofsky performance status scores. VAS data were analyzed using a linear statistical model. Breakthrough pain data were analyzed using analysis of variance (ANOVA).
                There were no statistically significant differences between IRM and SRM treatments with respect to VAS pain scores, side effect scores, or incidence of breakthrough pain data. Karnofsky performance scores remained stable for all patients throughout the study.
                It was concluded that every-12-hour administration of SRM and every-4-hour administration of IRM provide similar analgesic effectiveness and side effect profiles in the treatment of chronic pain in cancer patients. Twenty-three adult patients with chronic pain due to cancer completed a double-blind, randomized, two-phase crossover trial comparing plasma morphine concentrations and analgesic efficacy of oral morphine sulfate solution (MSS) and controlled-release morphine sulfate tablets (MS Contin [MSC], Purdue Frederick, Inc., Toronto, Ontario, Canada). MS Contin was given every 12 hours to all patients except those whose daily morphine dose could not be equally divided into two 12-hour doses with the tablet strengths available. MSS was given every 4 hours. Patients received both of the test drugs for at least 5 days, and, on the final day of each phase, peripheral venous blood samples for morphine analysis were obtained. Eighteen patients received MSC every 12 hours, and five received it every 8 hours. The same total daily morphine dose was given in both phases. In the 18 patients who received MSC every 12 hours, the daily morphine dose was 183.9 +/- 140.0 mg (mean +/- SD). In this group, the mean area under the curve (AUC) with MSC was 443.6 +/- 348.4 ng/ml/hour, compared with 406.8 +/- 259.7 ng/ml/hour for MSS (P greater than 0.20). Mean maximum morphine concentrations (Cmax) for MSC and MSS were 67.9 +/- 42.1 and 58.8 +/- 30.3 ng/ml, respectively (P greater than 0.05). Mean minimum morphine concentrations (Cmin) were 17.0 +/- 17.7 and 18.3 +/- 15.0, respectively (P greater than 0.30). There was a significant difference (P less than 0.001) between the two drugs in time required to reach maximum morphine concentration (Tmax). Mean Tmax after MSC occurred at 3.6 +/- 2.3 hours. After MSS, it occurred at 1.3 +/- 0.4 hours. In the five patients who received MSC every 8 hours, the findings paralleled those in the principal group, with no significant differences between MSC and MSS in Cmax or Cmin and a highly significant difference between the two in Tmax. However, in this small group of patients, the AUC with MSC was significantly (P = 0.04) greater than that with MSS. All patients had very good pain control throughout the study and both formulations were well tolerated. There were no significant differences between MSC and MSS in pain scores or side effects. Under the conditions of this study there was no clinically significant difference in bioavailability between MSC and oral MSS. When given on a 12-hourly basis in individually titrated doses, the MSC provided therapeutic plasma morphine concentrations throughout the dosing interval. Eighteen of 27 patients with pain due to advanced cancer, completed a randomised crossover comparison of 4-hourly aqueous morphine sulphate and twice daily controlled release morphine tablets. There was no difference between the two regimens in analgesic efficacy or adverse effects, but there was an apparent improvement in quality of sleep on the controlled release tablets. After completion of the study, 17 patients continued with the latter medication for periods that ranged from 2 days to 94 weeks (median 6.5 weeks). Controlled release morphine tablets given twice daily provide a simpler and more convenient treatment regimen than a 4-hourly opioid for patients with cancer pain, once they have been stabilised. Use of oxycodone for chronic cancer pain has been hampered by its short elimination half-life. This study was designed to compare the efficacy and safety of controlled-release formulations of oxycodone and morphine for cancer pain.
                Thirty-two adult patients with cancer pain and a > or = 3-day history of stable analgesia with oral opioids provided written informed consent and were randomized to controlled-release oxycodone or controlled-release morphine for 7 days. To blind the study using available tablet strengths, the dose ratio of oxycodone to morphine was set at 1:1.5. On day 8, patients were crossed over to the alternate drug for 7 days. Pain intensity was assessed using a visual analog scale (VAS 0 to 100 mm) and a categorical scale (CAT 0 to 4). Side effects were assessed using a checklist (four-point categorical severity) and a nondirected questionnaire. Patients and investigators made blinded global ratings of efficacy and treatment preference.
                Twenty-three patients completed the study (10 men, 13 women). The VAS and CAT scores were (mean+/-SD) 23+/-21 and 1.2+/-0.8 on controlled-release oxycodone, and 24+/-20 (P=.43) and 1.3+/-0.7 (P=.36) on controlled-release morphine. No period or carryover effect was detected. There were no significant differences in adverse effects (P=.40) or ratings of efficacy and preference. The median oxycodone/morphine dose ratio was 1.5 and the maximum was 2.3.
                Controlled-release oxycodone is as safe and effective as controlled-release morphine in the treatment of cancer pain. The efficacy, safety, and pharmacokinetics of a novel once-daily morphine formulation (OAD morphine) and a 12-hourly formulation (twice-daily CR morphine) were compared in a double-blind, multi-centered crossover study. Chronic cancer pain patients (n=25) were randomized to OAD morphine (mean 238 +/- 319 mg q24h) or twice-daily CR morphine (mean 119 +/- 159 mg q12h) for one week. They then crossed over to the alternate drug, which also was taken for one week. There was no difference between treatments for evaluations of overall pain intensity, analgesic efficacy, or adverse events. However, whereas pain scores increased during the day on twice-daily CR morphine (P=0.0108), they remained stable on OAD morphine. Most patients (68%) chose once-daily dosing for continuing pain management (P=0.015). The AUC ratio was 100.3%, indicating equivalent absorption. Fluctuation indices were 93.5 +/- 28.8% and 179.3 +/- 41.3% (P=0.0001) for OAD morphine and twice-daily CR morphine, respectively. OAD morphine provides analgesia similar to twice-daily CR morphine with reduced fluctuation in plasma morphine concentration and more stable pain control. Recently a sustained-release morphine sulfate tablet (MS Contin [MSC]) was introduced in Canada. In a randomized double-blind crossover trial we compared MSC given every 12 hours with a morphine sulfate solution (MSS) given every 4 hours to 17 patients suffering from chronic severe pain. After titration of the morphine dosage to optimize the analgesic effect, each patient received 10 days of therapy with either MSC or MSS, then 10 days of therapy with an equal daily dose of the other formulation. Both preparations provided effective pain control, with minimal side effects. There was no significant difference between MSC and MSS in pain scores on a visual analogue scale (VAS), severity scores for tiredness and nausea, amount of supplemental morphine needed for break-through pain or patient preference. The plasma morphine concentrations tended to be greater during treatment with MSC. The study had an 89% probability of detecting a clinically significant difference in VAS pain scores. We conclude that an individualized, twice-daily regimen of MSC is as effective as MSS given every 4 hours for control of severe pain. The twice-daily regimen has several advantages: it provides for an uninterrupted night's sleep, it is substantially more convenient than the six doses per day required with MSS, and it should help reduce both medication errors and noncompliance. A double-blind, double-dummy, crossover study compared oral controlled-release morphine sulfate (MS Contin tablets [MSC], Purdue Frederick, Norwalk, CT) every 12 hours, and immediate-release morphine sulfate (IRMS) tablets, every 4 hours, in 14 evaluable patients with chronic cancer pain. The test model described showed assay sensitivity for steady-state analgesia, requiring relatively few subjects to yield statistical significance in pharmacologic potency estimates. Initial doses were the calculated equivalents of about one third the previous opioid requirements or at least 30 mg MSC every 12 hours or 15 mg IRMS every 4 hours. This was generally subtherapeutic; hence, additional IRMS was available for break-through pain. Doses of MSC and IRMS were titrated upwards until the requirement for rescue IRMS was less than 20% of the total daily amount of morphine. In both study phases, the total dose of morphine increased significantly from the first day to the last, on which it was significantly (34%) higher for IRMS than MSC. Pain was significantly less intense and frequent in the last 24 hours of each treatment arm than in the first, and equally well controlled by both regimens. The two treatments were equipotent in a pharmacologic assay using dosages and pain scores. The requirement for rescue analgesia was similarly comparable for both treatments, decreasing significantly with upward dose titration. The few side effects experienced (one with MSC and three with IRMS) did not include serious reactions such as respiratory depression. It is concluded that MSC, 12-hourly, controls cancer pain as effectively and safely as IRMS on a 4-hour schedule. MS Contin exhibits a 12-hour duration of action as previously shown in other well-controlled trials. A problem of pain exacerbation at the start of each study phase was found to be associated with the design of this study. It may be resolved with a higher initial study dose and/or use of a patient-controlled analgesia device for parenteral rescue doses. Oncology nursing is concerned with pain relief and overall Quality of Life (QOL). The purpose of this study was to determine the effects of controlled-release morphine on QOL for patients with cancer. Eighty-three subjects were randomly assigned in a clinical trial of short-acting versus controlled-release analgesia (MS Contin, Purdue Frederick Co., Norwalk, CT). Data was collected in a repeated measures design every 2 weeks for 6 weeks yielding a total of 240 visits. Five instruments were used to assess QOL, pain, and functional status. Study findings indicate improved pain management with controlled-release MS Contin and important nursing implications for the management of analgesia-induced gastrointestinal symptoms. Through appropriate pain management with pain therapies such as controlled-release analgesia, nurses can greatly enhance QOL for the patient with cancer. The role of opioids for moderate pain (so-called "weak" opioids) in the second step of the World Health Organization's analgesic ladder has been investigated in a prospective randomized study. Sixteen patients were administered dextropropoxyphene (DPP) in a dosage ranging from 120 mg to 240 mg daily (group 1), and 16 patients were administered the lowest doses (20 mg daily) of commercially available controlled-release morphine (group 2). Equianalgesic doses of oral morphine, pain relief, and symptoms during the first 10 days of therapy and during the last 4 weeks before death were assessed. Three of 16 patients maintained DPP until death, whereas three patients in group 2 were switched to DPP due to the occurrence of intolerable side effects. Intensity and frequency of nausea and vomiting, drowsiness, and dry mouth were higher in group 2 than in group 1 during the initial treatment. These results stress the role of "weak" opioids during the induction of opioid therapy in opioid-naive cancer patients. Although the oral route is the preferred method of opioid therapy in patients with cancer pain, many patients will require an alternate route of analgesic administration at some point during the trajectory of their illness. This study compared the efficacy and safety of a novel, controlled-release suppository of morphine (MSC-R) and controlled-release morphine tablets (MSC-T) in patients with cancer pain. In a double-blind crossover study, 27 patients with cancer pain were randomized to receive MSC-R or MSC-T every 12 hours for 7 days each, using a 1:1 analgesic equivalence ratio. Pain intensity was assessed using a visual analog scale (VAS) and the Present Pain Intensity Index of the McGill Pain Questionnaire. Nausea and sedation were also assessed with a VAS. Pharmacodynamic assessments were made by the patient at 8:00 AM, 12:00 PM, 4:00 PM, and 8:00 PM and rescue morphine use recorded in a daily diary. There were no significant differences between MSC-R and MSC-T in overall scores for pain intensity VAS, ordinal pain intensity, and sedation. There was a small but significant difference in overall nausea VAS score in favor of MSC-R. Mean daily rescue analgesic use did not differ significantly during between treatment with MSC-R and MSC-T. MSC-R provides pain control comparable to that provided by MSC-T when given every 12 hours at a 1:1 dose ratio, and represents a reliable alternative method of pain control for patients unable to take oral opioid agents. The antinociceptive effect of morphine and oxycodone is mediated preferentially at micro and kappa receptors, respectively. The aim of this study was to evaluate the analgesic profile of the combination of morphine and oxycodone in cancer pain, compared to the standard administration of morphine alone. Controlled-release formulations of oxycodone (CRO) and morphine (CRM) were compared in 26 patients. The study started with an open-label, randomised titration phase to achieve stable pain control for 7 days, followed by a double-blind, randomised crossover phase in two periods, 14 days each. At any point, patients were allowed to use oral immediate-release morphine (IRM) as needed, in order to keep visual analogue scale < or =4. Pain, satisfaction, adverse effects and number of daily rescue morphine tablets were assessed. A total of 22 patients were evaluated. The weekly upload consumption ratio in morphine/oxycodone was 1 : 1.8 (1.80, 1.83, 1.76, 1.84). The weekly IRM consumption was higher in patients having CRM compared to patients having CRO (ratio morphine/oxycodone: 1.6, 1.6, 1.6, 1.7) (P<0.05). Patients receiving oxycodone complained of less nausea and vomiting. The rescue morphine analgesic consumption was 38% higher in patients receiving only morphine, compared to patients receiving both morphine and oxycodone. The results suggest that the combination of morphine/oxycodone (opioids with differential preferential sites of action) can be a useful alternative to morphine alone, resulting in a better analgesia profile and less emesis. Cancer patients requiring strong opioid analgesia (n = 202; mean age, 61.5 years; range, 18-89 years; 55% men) were recruited from 38 United Kingdom palliative care centers into a randomized, open, two-period, crossover study comparing transdermal fentanyl with sustained-release oral morphine. Patients received one treatment for 15 days followed immediately by the other for 15 days. Daily diaries were completed. Both treatments appeared equally effective in terms of pain control, as assessed by the Memorial Pain Assessment Card and European Organization for Research and Treatment of Cancer (EORTC) pain scores. Fentanyl was associated with significantly less constipation (p < 0.001) and less daytime drowsiness (p = 0.015) but greater sleep disturbance (p = 0.004) and shorter sleep duration (p = 0.008) than morphine. The World Health Organization (WHO) performance status and EORTC global quality of life scores showed no significant difference between treatment groups. Of those patients who were able to express a preference (n = 136), significantly more preferred the fentanyl patches (p = 0.037). We conclude that, in this study, transdermal fentanyl provided pain relief that was acceptable to cancer patients and was associated with less constipation and sedation than morphine. These reduced side effects may contribute to patients preference for the patches. Oxycodone is an opioid analgesic that closely resembles morphine. Oxymorphone, the active metabolite of oxycodone, is formed in a reaction catalyzed by CYP2D6, which is under polymorphic genetic control. The role of oxymorphone in the analgesic effect of oxycodone is not yet clear. In this study, controlled-release (CR) oxycodone and morphine were examined in cancer pain. CR oxycodone and morphine were administered to 45 adult patients with stable pain for 3-6 days after open-label titration in a randomized, double-blind, cross-over trial. Twenty patients were evaluable. Both opioids provided adequate analgesia. The variation in plasma morphine concentrations was higher than that of oxycodone, consistent with the lower bioavailability of morphine. Liver dysfunction affected selectively either oxycodone or morphine metabolism. Three patients with markedly aberrant plasma opioid concentrations are presented. Significant individual variation in morphine and oxycodone metabolism may account for abnormal responses during treatment of chronic cancer pain. Opioid and spinal monoaminergic agonists have distinct analgesic properties, which may potentiate each other. Tramadol has both opioid and monoaminergic agonist actions. This initial study compared the analgesic and toxic effects of tramadol and morphine in patients with strong cancer pain.
                Pain control and side-effects with tramadol and morphine were compared in 20 cancer patients hospitalised for the treatment of strong pain. Doses of oral solutions of tramadol or morphine were individually titrated in the double-blind, randomized, cross-over study. Cross-over was after day 4, the day of statistical evaluation.
                The mean pain intensity (+/- SD) on a verbal rating scale (0 = none, 4 = unbearable) was similar with morphine (1.6 +/- 1.2, n = 17) and with tramadol (1.5 +/- 1.3, n = 16) on the fourth day of dosing. The mean daily doses on day 4 were 101 +/- 58 mg of morphine and 375 +/- 135 mg of tramadol, indicating a relative potency of 4:1 with oral dosing. The total number of side-effects per person was lower on the fourth day with tramadol (p < 0.05), as was the severity of nausea (p < 0.05) and constipation decreased with tramadol (p < 0.05). Three patients dropped out of the morphine group due to side-effects and 4 out of the tramadol group due to inadequate analgesia. Overall, 8 patients (40%) preferred morphine, 3 (15%) favoured tramadol and 9 (45%) expressed no distinct choice. Nurses rated pain control better with morphine (p < 0.03), but the tolerability of tramadol was judged superior (p < 0.002).
                In certain cancer patients with strong pain, tramadol achieved good pain control with fewer side-effects than morphine. The non-opioid mode of action may result in a different spectrum of analgesia and side-effects. Longterm studies are required to confirm this study of brief duration. The efficacy, tolerability and 24-h duration of action of MXL capsules, a novel once-daily morphine preparation, were compared with twice-daily morphine tablets (MST Continus tablets) in patients with severe cancer pain. Eighty-five patients were recruited to this randomized, double-blind, double-dummy, crossover study. There was no significant difference between the two treatment groups in the number of occasions that escape medication was required, the pain scores at each of three time points throughout the day, and the number of nights woken due to pain. Both preparations were well tolerated with no significant difference in the number or severity of reported symptoms and side-effects. Sixteen patients withdrew from the study, of whom 13 withdrew for nontreatment-related reasons. There was no difference between the preparations in terms of expressed treatment preference. MXL capsules were shown to provide effective analgesia over the 24-h dosing interval which was comparable to that of MST Continus tablets administered twice daily. Twenty-four patients with severe pain related to cancer completed a randomised, double-blind, double-dummy, crossover study examining morphine pharmacokinetics and pharmacodynamics when the same 24-h morphine dose was administered using two modified release oral morphine formulations; either one dose of Kapanol (a new sustained release polymer coated pellet formulation administered in capsule form, Glaxo Wellcome group of companies) per 24 h, or MS Contin (Purdue Frederick Company, Connecticut, USA) administered at 12-h intervals. The morphine dose was optimised for each patient using an immediate release morphine solution in the lead-in period to provide the most favourable balance between pain relief and side-effects. Patients were then randomly allocated to receive their 24-h morphine dose as either Kapanol or MS Contin in period 1. Patients recorded daily measures of pain relief and morphine related side-effects (morphine pharmacodynamics) in a diary. Patients were admitted to the Pain Management Unit on the morning of day 7 (+/- 1 day) and frequent blood samples were collected for 24 h following the 10:00 h dose to fully characterise the pharmacokinetic profile for morphine and its metabolites at steady state. Morphine pharmacodynamics and the amount and timing of rescue medication (dextromoramide) were also recorded during this time. Period 2, which commenced at 10:00 h on day 8, was identical to period 1 except the modified release formulations were changed. The pharmacokinetic profile of Kapanol exhibited a significantly higher Cmin (minimum plasma morphine concentration), less fluctuation in plasma morphine concentration throughout the dosing interval, a longer Tmax (time associated with the maximum morphine concentration) and a greater time that the plasma morphine concentration was > or = 75% of Cmax (an index of the control the formulation exerts over the morphine release rate) compared to that of MS Contin. Some of these pharmacokinetic differences (e.g., Cmin and fluctuation in plasma morphine concentration) were surprising given that the dosing interval for Kapanol (24 h) was double that of MS Contin (12 h). There was no significant difference between the Kapanol and MS Contin treatment phases in any of the pharmacodynamic parameters, morphine related side-effects, the percentage of patients taking rescue medication as well as the amount or time to the first dose of rescue analgesia on day 7 in periods 1 and 2, patient or investigator assessments of global efficacy at the end of periods 1 and 2, or patient treatment preference at the end of the study. Once a day Kapanol provided the same degree of pain relief and morphine related side-effects as 12-h MS Contin. Kadian/Kapanol (K) is a capsule formulation of morphine designed for 12- or 24-hourly dosing. This double-blind study compared the efficacy and safety of K every 24 hr to K every 12 hr and MS Contin tablets (MSC) every 12 hr. One hundred fifty-two patients with cancer pain were titrated to adequate analgesia with immediate-release morphine (IRM) solution. Stabilized patients were randonized to one of the three treatments for 7 +/- 1 days. Rescue medication was IRM tablets. Efficacy and safety were assessed by time to first remedication and total dose of rescue medication, pain scores, global assessments, and incidence of morphine-related side effects. Fifty-four patients were treated with K every 24 hr. 45 with K every 12 hr. and 53 with MSC every 12 hr. Mean age was 61 years and mean total daily dose of morphine was 138 mg. Forty-six percent of the K every 24 hr patients, 51% of the K every 12 hr patients, and 55% of the MSC every 12 hr patients required rescue medication on the final day. Time to remedication was 16.0 hr for K every 24 hr, 9.1 hr for K every 12 hr and 8.7 hr for MSC every 12 hr (P = 0.0010). Patient global assessment significantly favored K every 24 hr over MSC every 12 hr (P = 0.018). There were no statistically significant differences among the treatments for any morphine-related side effects when adjusted for baseline. K had efficacy and safety profiles similar to MSC every 12 hr but had the advantage of 12- or 24-hourly administration. In order to determine the optimal pain treatment for patients with cancer involvement of the brachial or lumbar nerve plexuses, a prospective comparative study was carried out using peroral opioid therapy (SO), epidural opioid by a conventional tunnelled epidural catheter (CE) or an epidural catheter connected to an implanted injection port (Port). Pain relief, measured by a visual analog scale (VAS), was similar and adequate in every group already after the first 24 h. CNS side-effects were less frequent and the Karnofsky performance grades slightly superior in the epidural groups. Occlusion and catheter disconnection complicated the pain therapy of five epidural port patients. Epidural dislocation occurred three times in the conventional epidural group. One local infection in the CE group and two in the Port group were recorded. However, no signs of epidural infection were seen at autopsy. The results suggest that due to a lower incidence of side-effects, epidural catheter techniques are superior to peroral opioid in treating pain in these patients. However, complete pain relief was not achieved in all patients, suggesting neurogenic, non-nociceptive pain components. Both epidural techniques seem suitable for long-term pain therapy. Technical improvements are needed in the epidural catheter and the port. The long-term epidural catheter does not seem to cause any major changes in the histology of the dura mater or the connective tissue of the epidural space. Nineteen of 25 patients (14 female) with advanced malignant disease completed a randomized controlled trial of a new high-dose (200 mg) tablet formulation of controlled-release morphine. Compared with the currently available 100-mg tablets there were no differences in pain severity or adverse effects with the new formulation. In four patients, full 12-hr plasma morphine concentration profiles at steady state were obtained and showed no significant differences between the same dose provided as 100-mg and 200-mg tablets in Cmax, tmax, or other pharmacokinetic indices. The MS Contin tablet 200 mg (controlled release morphine sulphate) provides an equivalent rate and extent of absorption to two MS Contin tablets 100 mg. The characteristics of controlled release from this higher strength formulation are also consistent with those of the 100 mg tablet. The level of analgesia provided during the early post-dosing period, at the end of the dosing period and overall over the twelve hour interval were also equivalent between the preparations. The addition of the MS Contin tablet 200 mg to the existing range will facilitate oral dosing in patients requiring large doses of morphine. This extension to the range will increase the choice available to the clinician and provide a natural progression for those patients requiring a step-up in the dose titration procedure. Controlled-release (CR) formulations of oxycodone and morphine were compared in 45 patients with chronic cancer pain. The study was started with an open-label, randomised titration phase to achieve stable pain control for at least 48 h, followed by a double-blind, randomised, crossover phase in two periods, 3-6 days each. To blind the study using available tablet strengths, the dose ratio of oxycodone to morphine was set at 2:3. A daily telephone contact was maintained between the patient and the investigator. The patients were asked to assess pain intensity four times a day and acceptability of therapy twice daily, and to record possible adverse effects. Pharmacodynamic evaluations were performed at the end of each double-blind period. The patients were allowed to use escape analgesic (respective opioid as oral solution) as needed. Twenty-seven patients were evaluable for both safety and efficacy. Pain was well-controlled during both stable phases. When the period effect was taken into account the two opioids provided comparable analgesia. If the results of the two periods were combined, the patients consumed significantly more escape doses and the mean pain intensities were significantly greater with CR oxycodone. The total opioid consumption ratio of oxycodone to morphine was 2:3 when oxycodone was administered first, and 3:4 when oxycodone was administered after morphine. The total incidence of adverse experiences reported by the patients was similar, but significantly more vomiting occurred with morphine, whereas constipation was more common with oxycodone. Sustained-release morphine (MST) given by the rectal route was compared with oral MST in an open randomised cross-over trial in ten patients with cancer who received stable doses of MST. No significant difference was found in the areas under the curve of the concentration-time profiles (AUC) following oral or rectal administration for parent morphine. The AUCs determined for morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) after oral administration were approximately twice those obtained following rectal administration. The maximal concentration achieved was lower and the time to maximal concentration was longer following rectal administration for morphine, M6G and M3G. The relative mean arrival times following rectal administration were significantly longer for morphine and M3G but not for M6G. These findings suggest slower absorption but less first-pass metabolism of MST after rectal administration. No significant difference was noted between the oral and the rectal route in measurements on visual-analogue scales for pain or side effects. We recommend the rectal route as being suitable for MST administration when the oral route is no longer available. In changing from oral to rectal administration, the same dose and dose interval may be used, but dose adjustment may be needed. Controlled-release morphine (MST) given twice daily provides a simpler and more convenient treatment regimen than 4-hourly opioid administration for the control of cancer pain. Recently, a new formulation of transdermal fentanyl (TDF) has been developed which provides a new route for the treatment of cancer pain. The present study was designed to compare the analgesic efficacy, safety and adverse effects of MST and TDF in the management of chronic cancer pain.
                In this open, comparative and randomized study, patients were treated with oral morphine hydrochloride immediate-release (MHIR) in the stabilization phase and then the prescription was switched to MST or TDF for 14 days in the treatment phase. Oral MHIR was provided as rescue medication for breakthrough pain. Assessments of the pain intensity, pain frequency, degree of pain improvement, profile of mood states, quality of sleep, activity status and adverse effects were performed before and after the stabilization phase and before and after the treatment phase.
                Forty of 47 cancer patients completed the study with 20 patients in each group. There were significant (p < 0.05) improvements in pain intensity, pain frequency, mood states and quality of sleep in both groups before and after treatment, while improvement in the activity status was not significant. No specific adverse effects were encountered except for drowsiness which occurred in 6 patients treated with MST and 5 treated with TDF (p < 0.05). Insomnia was significantly improved (p < 0.05) with both regimens compared with that in the period before treatment. There were no significant differences between the two study groups in analgesic efficacy or adverse effects.
                These results suggest that TDF and MSt are safe and effective analgesics for the management of chronic cancer pain. However, TDF provides a simpler and more convenient treatment for those patients with severe nausea, vomiting or dysphagia. Fifty-one cancer pain patients with limited opioid exposure participated in a randomized, double-blind, repeated-dose, parallel-group comparison of two dosage strengths of the controlled-release morphine preparation, MS Contin tablets (The Purdue Frederick Company, Norwalk, CT). The patients were first stabilized on immediate-release oral morphine 30 mg every 4 hours, with 15 mg available every 2 hours as needed for breakthrough pain ("rescue" dose). Each patient then received either one 100 mg MS Contin tablet or three 30-mg MS Contin tablets every 12 hours, with rescue medication as needed, for 3 days. Analysis of study power revealed sufficient sensitivity to detect clinically relevant differences in pain intensity and use of rescue medication. The two tablet strengths yielded similar pain relief, use of rescue medication, and frequency of side effects. In addition, pain and use of rescue medication did not change from the beginning to the end of the 12-hour dosing intervals in either group. In the study population as a whole, pain intensity was lower and total morphine intake higher during the period on controlled-release morphine. These data establish comparable analgesic efficacy and side effect potential of these two dosage strengths and confirm a 12-hour duration of effect for both. The improved analgesia on the controlled-release morphine may be attributable to increased consumption of drug resulting from improved compliance. The authors report the data from two studies on the use of controlled-release morphine sulphate tablets for cancer pain relief. This preparation allows just two administrations per day, in comparison with immediate release oral aqueous morphine solution. The first study, a randomized trial carried out on 70 patients suffering from advanced cancer pain, evaluated the analgesic efficacy and side effects of this drug. The second, an open study of 113 patients, assessed analgesic efficacy, incidence of side effects, and the effects of age on dose. The analgesia provided by controlled-release morphine administration proved to be superimposable to those of the oral aqueous morphine solution. Moreover, the use of controlled-release morphine was associated with a statistically significant reduction of some side effects. Ninety-one percent of patients needed controlled-release morphine every 12 hr, while 9% required it every 8 hr. We compared the effects of controlled-release and immediate-release morphine preparations in adult patients with moderate-to-severe cancer pain and report methodologic approaches to pain evaluation. The study consisted of a two-phase randomized crossover trial preceded by a titration phase; all phases were conducted under double-blind conditions. To evaluate pain intensity, a visual analogue scale (VAS) and the Present Pain Intensity scale of the McGill Pain Questionnaire were used. Additional morphine solution for breakthrough pain was used as an outcome measure. Pain was evaluated nine times daily, which permitted correlation of pain scores with the pharmacokinetic patterns of the test drugs. Side effects were rated once daily, using a scale from 0 to 3. To assess the relative importance of side effects, a toxicity index was designed based on both the intensity and duration of each side effect. The overall VAS pain scores during treatment with controlled-release and immediate-release morphine were 1.3 (SD = 0.1) and 1.4 (SD = 0.2), respectively. Use of supplemental morphine solution for breakthrough pain expressed as the percentage of the daily dose of the test drug was 5.5% for the controlled-release drug and 10.9% for the immediate-release drug. Differences in pain scores, side effects, and supplemental morphine requirement between the two groups were not significant. We discuss methodologic issues in double-blind clinical trials of analgesics, in particular the validity of "Patient Preference" as an outcome measure and problems related to the titration phase. nan Oral transmucosal fentanyl citrate (OTFC); Actiq) is a drug delivery formulation used for management of breakthrough cancer pain. Previous studies with open-label comparisons indicated OTFC was more effective than patients' usual opioid for breakthrough pain. The objective of this study was to compare OTFC and morphine sulfate immediate release (MSIR) for management of breakthrough pain in patients receiving a fixed scheduled opioid regimen. This double-blind, double-dummy, randomized, multiple crossover study was conducted at 19 US university- and community-based hospitals and clinics and comprised 134 adult ambulatory cancer patients. Patients were receiving a fixed scheduled opioid regimen equivalent to 60-1000 mg/day oral morphine or 50-300 microg/h transdermal fentanyl, were using a 'successful' MSIR dose (15-60 mg) as defined by entry criteria, and were experiencing 1-4 episodes of breakthrough pain per day. In open-label fashion, OTFC was titrated such that a single unit (200-1600 microg) provided adequate pain relief with acceptable side effects. Successfully titrated patients entered the double-blind phase of the study and received ten prenumbered sets of randomized capsules and oral transmucosal units. Five sets were the successful OTFC dose paired with placebo capsules, and five sets were placebo OTFC paired with capsules containing the successful MSIR dose. Patients took one set of study medication for each episode of target breakthrough pain. Pain intensity (PI), pain relief (PR) and global performance of medication (GP) scores were recorded. Pain intensity differences (PID) were calculated and 15-min PID was the primary efficacy variable. Adverse events were recorded. Sixty-nine percent of patients (93/134) found a successful dose of OTFC. OTFC yielded outcomes (PI, PID, and PR) at all time points that were significantly better than MSIR. GP also favored OTFC and more patients opted to continue with OTFC than MSIR following the study. Somnolence, nausea, constipation, and dizziness were the most common drug-associated side effects. In conclusion, OTFC was more effective than MSIR in treating breakthrough cancer pain. Nineteen patients with pain from advanced cancer stabilised on oral 4-hourly aqueous morphine who were to be converted to twice daily controlled-release morphine tablets (MST Continus) completed this study. Patients were randomised to receive either their usual 4-hourly morphine dose or placebo with the first dose of MST tablets. There were no significant differences between the treatment groups in ratings of pain intensity, pain relief or side effects, or in any of the measured pharmacokinetic parameters. No patients in the placebo group experienced any breakthrough pain, and nursing staff were unable to identify which patients had received the active dose of morphine elixir. We conclude that there is no need for a loading dose when aqueous morphine is changed to MST tablets. In a double-blind, randomised and parallel clinical trial, two oral doses of dipyrone (1 and 2 g) administered every 8 h were compared with 10 mg of oral morphine given every 4 h for the relief of chronic cancer pain. A total of 121 patients with cancer pain without gastric involvement participated in a 7-day treatment course and were allocated to receive either dipyrone 1 g (n = 41), dipyrone 2 g (n = 38) or morphine (n = 42). Drug efficacy was analysed according to the degree of pain relief using a 100-mm visual analogue scale, and the number of patients who decided to increase the dose of the analgesic drug on day 4. The analgesic effect of dipyrone, 2 g every 8 h, was similar to that of morphine. The efficacy of both schedules was significantly greater than that of dipyrone, 1 g every 8 h. Dipyrone at either 1 or 2 g doses tended to be better tolerated than morphine, although the differences were not statistically significant. Nineteen cancer patients with chronic pain of moderate to severe intensity were randomized in a double-blind manner to 5 days of either 8-hourly or 12-hourly administration of controlled-release morphine (MS Contin, MSC), followed by the alternate schedule for 5 days. The control of pain, using an average dose of 303.4 +/- 254.4 mg/day of MSC, was good during both the 8-hourly and 12-hourly phases, and the mean daily pain intensity measured by visual analogue scale (VAS), pain relief (VAS), and global efficacy scores did not differ when compared by treatment schedule. The need for supplemental "rescue" morphine was infrequent and did not differ between treatment phases (8-hourly, 0.7 +/- 0.7 and 12-hourly, 0.6 +/- 0.6 doses per day, p = 0.6232). The overall frequency and severity of adverse events did not differ between the two dosing schedules. A majority of patients (67%) reported that they believed that 12-hourly dosing was a moderate or great advantage over 8-hourly dosing. nan Controlled-release oral formulations of oxycodone and morphine are both suitable analgesics for moderate to severe pain. They were compared in cancer-pain patients randomized to double-blind treatment with controlled-release oxycodone (n = 48) or controlled-release morphine (n = 52) every 12 h for up to 12 days. Stable analgesia was achieved by 83% of controlled-release oxycodone and 81% of controlled-release morphine patients in 2 days (median). Following titration to stable analgesia, pain intensity (0=none to 3=severe) decreased from baseline within each group (p </= 0.005), from 1.9 (0.1) to 1.3 (0.1), mean (SE), with controlled-release oxycodone, and from 1.6 (0.1) to 1.0 (0.1) with controlled-release morphine (no significant between-group differences). Typical opioid adverse experiences were reported in both groups. Hallucinations were reported only with controlled-release morphine (n = 2). Visual analog scores (VAS) for 'itchy' and 'scratchin' were lower with controlled-release oxycodone (p </= 0.044), as was peak-to-trough fluctuation in steady-state plasma concentration (p = 0.004). The correlation between plasma concentration and dose was stronger (p = 0.026) for oxycodone (0.7) than morphine (0.3). The relationship between pain intensity (VAS) and plasma concentration was more positive for oxycodone (p = 0.046). There was a positive relationship between morphine-6-glucuronide concentrations and urea nitrogen and creatinine levels (p = 0.001). Controlled-release oxycodone was as effective as controlled-release morphine in relieving chronic cancer-related pain, and as easily titrated to the individual's need for pain control. While adverse experiences were similar, controlled-release oxycodone was associated with less itching and no hallucinations. Controlled-release oxycodone provides a rational alternative to controlled-release morphine for the management of moderate to severe cancer-related pain. The Brompton mixture is widely used as an effective method for controlling pain in cancer patients. In a double-blind crossover trial a standard Brompton mixture containing morphine, cocaine, ethyl alcohol, syrup BP and chloroform water was compared with morphine alone in a flavoured aqueous solution; both were administered orally. Pain was measured by means of the pain intensity index of the McGill Pain Questionnaire. Ratings of confusion, nausea and drowsiness were obtained from both the patients and their nurses and relatives. The data showed that there was no significant difference between the Brompton mixture and morphine administered orally for any of the variables. Both relieved pain effectively in about 85% of the patients. In a double-blind crossover study, morphine and oxycodone hydrochloride were administered to 20 patients who were experiencing severe cancer pain. The peroral doses were determined on the basis of patient-controlled intravenous titration. The assumed oral bioavailability ratios were 44% (group 1, first 10 patients) and 33% (group 2, last 10 patients) for morphine and 66% (group 1) and 50% (group 2) for oxycodone hydrochloride, respectively. However, the patients were able to readjust their oral dosings. Equal analgesia was achieved with both drugs, but the intravenous dose of oxycodone hydrochloride needed was 30% higher than that of morphine. The median calculated oral/intravenous ratios giving comparable analgesia were 0.31 for morphine and 0.70 for oxycodone hydrochloride. Morphine caused more nausea than oxycodone hydrochloride and hallucinations occurred only during morphine treatment. Otherwise, there were no major differences in the side effects between these two opioids. This study compared the efficacy and the adverse effects of controlled-release morphine (CRM) suspension (SAR 213) and CRM tablets (Moscontin) in the treatment of cancer pain. This multicenter, randomized, double-blind, double-dummy, crossover study was carried out on 52 patients. Each patient received both study treatments given at an equivalent dosage of morphine during each of two 7-day periods. The primary outcome variable was the severity of pain assessed three times daily by means of a visual analogue scale. Secondary criteria of efficacy were the severity of pain assessed by verbal rating scale, the need for "rescue" doses of immediate-release morphine, treatment preference, and indices of quality of life (activity, mood, sleep). There were no statistically significant differences in the parameters assessed when comparing the two groups. This study shows that, when prescribed at the same doses, CRM suspension and CRM tablets have similar efficacy and adverse effects, as well as the same duration of action. The results of this first clinical study carried out on CRM suspension are especially relevant for patients with cancer pain who have difficulty swallowing. This randomised, multicentre, direct open comparative trial evaluated the efficacy, treatment convenience, tolerability and safety aspects of transdermal therapeutic system (TTS)-fentanyl and sustained-release oral morphine (SRM) in both opioid-naïve patients with moderate-to-severe cancer-related pain and in patients who had already been using opioids for mild-to-moderate pain. The two treatment groups were run in parallel. Special attention was paid to constipation, nausea/vomiting, drowsiness and respiratory depression.
                The 131 enrolled patients started the 4-week treatment at low doses of opioid (25 microg/h TTS-fentanyl for 3 days or 30 mg SRM every 12 h) and were individually titrated. Tolerability, efficacy and safety were assessed throughout the study period. Frequency of constipation was the primary study variable and accordingly the study was powered for this. Both patients and investigators made a global treatment evaluation.
                TTS-fentanyl and SRM were shown to be equally effective. Pain control and sleep quality improved with both treatments. None of the patients developed respiratory depression. Statistically significantly more patients in the SRM treatment group discontinued the trial prematurely (59% vs 27%; p < 0.001), particularly due to adverse events (36% vs 4%; p < 0.001). Fewer patients in the TTS-fentanyl than in the SRM treatment group reported constipation during the trial. This finding was statistically significant after 1 week of treatment (27% vs 57%; p = 0.003). The favourable tolerability profile of TTS-fentanyl was also reflected in both the patient and the investigator global evaluation of the treatment. Patient assessment favoured TTS-fentanyl treatment in terms of a significantly lower rate of troublesome side-effects ('quite a bit' to 'very much' troublesome side-effects in 14% vs 36% of patients; p = 0.003) and less interruption of daily activities (absence of any interruption of daily activities in 88% vs 63% of patients; p = 0.012). Investigators scored TTS-fentanyl as significantly better with respect to 'side-effects' (p = 0.039) and 'overall impression' (p = 0.013). Sub-analyses of opioid-naïve users gave similar results.
                These data indicate that TTS-fentanyl, when used as an opioid of first choice in the treatment of cancer-related pain, is as effective as, but better tolerated than, SRM, including in opioid-naïve patients. To compare the effectiveness and side effects of methadone and morphine as first-line treatment with opioids for cancer pain.
                Patients in international palliative care clinics with pain requiring initiation of strong opioids were randomly assigned to receive methadone (7.5 mg orally every 12 hours and 5 mg every 4 hours as needed) or morphine (15 mg sustained release every 12 hours and 5 mg every 4 hours as needed). The study duration was 4 weeks.
                A total of 103 patients were randomly assigned to treatment (49 in the methadone group and 54 in the morphine group). The groups had similar baseline scores for pain, sedation, nausea, confusion, and constipation. Patients receiving methadone had more opioid-related drop-outs (11 of 49; 22%) than those receiving morphine (three of 54; 6%; P =.019). The opioid escalation index at days 14 and 28 was similar between the two groups. More than three fourths of patients in each group reported a 20% or more reduction in pain intensity by day 8. The proportion of patients with a 20% or more improvement in pain at 4 weeks in the methadone group was 0.49 (95% CI, 0.34 to 0.64) and was similar in the morphine group (0.56; 95% CI, 0.41 to 0.70). The rates of patient-reported global benefit were nearly identical to the pain response rates and did not differ between the treatment groups.
                Methadone did not produce superior analgesic efficiency or overall tolerability at 4 weeks compared with morphine as a first-line strong opioid for the treatment of cancer pain.
The randomised trial literature for morphine is small given the importance of this medicine. Most trials recruited fewer than 100 participants and did not provide appropriate data for meta-analysis. Trial design was frequently based on titration of morphine or comparator to achieve adequate analgesia, then crossing participants over in crossover design studies. It was not clear if these trials are sufficiently powered to detect any clinical differences between formulations or comparator drugs. Studies added to the review reinforce the view that it is possible to use modified release morphine to titrate to analgesic effect. There is qualitative evidence for effectiveness of oral morphine which compares well to other available opioids. There is limited evidence to suggest that transmucosal fentanyl provides more rapid pain relief for breakthrough pain compared to morphine.