|
Capsules and suppositories of methadone for patients on high-dose opioids for cancer pain: clinical and economic considerations |
Watanabe S, Belzile M, Kuehn N, Hanson J, Bruera E |
|
|
Record Status This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn. Health technology Administration of capsules and suppositories of methadone for patients on high-dose opioids for cancer pain.
Type of intervention Treatment and palliative care.
Economic study type Cost-effectiveness analysis.
Study population Advanced cancer patients. Primary cancer diagnosis included genitourinary (14), lung (13), gastrointestinal (9), head and neck (4), breast (3), haematological (2), unknown (2) and other (3). 46 patients had poor prognosis for pain control according to the Edmonton Staging System and 31 patients demonstrated neuropathic pain syndromes, 13 visceral pain syndromes, 2 bone/soft tissue pain syndromes and 4 demonstrated mixed pain syndromes.
Setting The setting was secondary care. The study was carried out at the Edmonton General Hospital Palliative Care Unit in Canada.
Dates to which data relate Dates for effectiveness analysis and resource use were not specified. The price date was not specified.
Source of effectiveness data The evidence for final outcomes was derived from a single study.
Link between effectiveness and cost data The costing was undertaken retrospectively on the same patient sample as that used in the effectiveness study.
Study sample Data were collected retrospectively from the charts of 50 consecutive advanced cancer patients who had been switched from high dose opioids (hydromorphone parental solution or hydromorphone powder) to methadone (capsules for 24 patients and suppositories for 26 patients). The average age of patients was 60.7 years, 28 patients were male and 22 were female. This could have constituted a random sample of patients who switched treatment but more information would be required to ascertain this. However, patients were not randomly switched to methadone and the main reasons for switching from high dose opioids to methadone were uncontrolled pain in 24 patients (48%), opioid toxicity in 8 cases (16%), pain and toxicity in 15 patients (30%), and other reasons in 2 patients (4%). Since, in addition, there was no control group, there was potential bias in the effectiveness results. Power calculations to determine the sample size were not stated.
Study design This was a before-and-after study using the same sample. Potential bias exists in such a study design given that it was difficult to ascertain whether the change in outcomes was, in fact, due to the intervention and not to a spontaneous change in the condition or other changes. The mean duration of the treatment was 43.8 days. Discontinuation of methadone treatment was due to death in 29 patients (58%), discharge from hospital for 9 patients (18%), toxicity in 8 cases (16%), and other causes in 4 cases (8%). The paper did not state whether the assessment of outcomes was blinded. However, this is unlikely since the study was carried out retrospectively.
Analysis of effectiveness The analysis of the clinical study was neither based on intention to treat, since the results took into account patients who had discontinued methadone treatment by switching from methadone due to toxicity, nor on treatment completers since the data did not include the days of outpatient treatment in the nine patients discharged home on methadone. The primary health outcomes used in the analysis were the dose of medication in mg per day and visual analogue scores for pain intensity. In addition, toxicities caused by methadone were documented.
Effectiveness results The average dose for patients on hydromorphone was 267.8mg (+/- 178.8) per day and 312.8mg (+/- 284.3) per day for patients on methadone. The dose ratio of methadone to subcutaneous hydromorphone was 1.07 (+/- 0.90) for the 24 patients using capsules and 1.88 (+/- 1.27) for the 26 patients on suppositories, (p=0.01). The visual analogue scores for pain intensity, on a scale from 0 to 100mm were 51 (+/- 22) for patients on hydromorphone and 40 (+/- 20) for patients on methadone. The difference in means for the visual analogue scores was statistically significant, (p=0.01). Toxicities observed during methadone treatment were 46 cases of constipation, 42 cases of sedation, 18 cases of nausea, 16 cases of confusion, 6 cases of hallucinations, 6 cases of respiratory depression, 5 cases of myoclonus, 4 cases of proctitis, 1 case of pulmonary edema and 4 other cases, with some patients reporting more than one side effect. For the six instances of respiratory depression, five occurred in the subset of 33 patients switched over in less than three days, compared to one of 17 patients switched over in three or more days, (p=0.34).
Clinical conclusions The authors concluded that comparable analgesia between methadone and morphine was achieved at a dose ratio much lower than the frequently recommended equianalgesic ratio of 1 to 1 for methadone to morphine. Pain intensity appeared to decrease on methadone, although these results should be accepted with caution due to bias present in the study design. The presence of respiratory depression in 6 of the patients was a cause of concern, given that this complication was not common with conventional opioids.
Measure of benefits used in the economic analysis Benefits were measured in terms of visual analogue scores for pain intensity on a scale from 0 to 100mm.
Direct costs Quantities were not reported separately from costs. Costs were not discounted since the time span was less than a year. Direct costs included the cost of treatment for methadone and hydromorphone. The cost boundary adopted was that of the hospital. The cost of treatment with methadone was calculated for the actual dose used each day when the treatment was no more than 20 days. For treatment of longer duration, the cost was estimated by assuming that the dose increased linearly from stable to maximum dose and then remained unchanged until the end of treatment. Costs of treatment with methadone included the drug, materials for capsule and suppository preparation and pharmacy and technician time. Cost of treatment with hydromorphone was calculated by assuming that the dose on the day prior to switchover remained unchanged until the end of the treatment. Costs were calculated using the price of the commercially available drug. The price year was not specified.
Statistical analysis of costs The difference in means of the two treatment costs was analysed using Student's t-tests.
Indirect Costs Indirect costs were not included in the analysis.
Sensitivity analysis No sensitivity analyses were performed.
Estimated benefits used in the economic analysis The mean visual analogue score for pain intensity for patients on methadone was 40 (+/- 20) and 51 (+/- 22) for patients on hydromorphone. The difference in means was statistically significant, (p=0.01). Incremental benefits were not reported. Side effects of treatment were not included in the estimated benefits, but toxicities due to methadone were documented. In particular the authors suggested that the increased effectiveness of methadone should be accepted with caution due to the occurrence of 6 cases of respiratory depression, a side-effect uncommon to hydromorphone treatment.
Cost results The cost of treatment was Can$116.77 (+/- 157.17) for methadone capsules, Can$105.33 (+/- 146.35) for methadone suppositories, Can$3,450.51 (+/- 5,098.58) for hydromorphone parenteral solution and Can$1,801.21 (+/- 2,661.52) for hydromorphone powder. Incremental costs were not reported but the difference in the mean costs between the two treatments was reported to be statistically significant, (p=0.0001).
Synthesis of costs and benefits Estimated costs and benefits were not combined. The intervention with methadone treatment dominated the intervention with hydromorphone treatment (increased benefits and lower costs).
Authors' conclusions The authors concluded that methadone was an effective, low-cost alternative for patients on high-dose opioids for cancer pain, but that the significant incidence of respiratory depression indicated a need for careful monitoring during the initial switchover and the titration phase of treatment.
CRD COMMENTARY - Selection of comparators The choice of hydromorphone as a comparator was justified by the authors as being the standard practice for palliative care for advanced cancer patients.
Validity of estimate of measure of benefit The main weakness of the study concerned the clinical study design. Before-and-after studies are prone to confounding, because the lack of a control group makes it impossible to ascertain whether the change in outcomes is due to the intervention or to other unknown factors. The results were also potentially biased because the patients were not randomly switched to methadone treatment. The results could have been strengthened by using statistical analyses to account for known potential confounders, such as primary cancer diagnosis, age and sex.
Validity of estimate of costs Not all categories of hospital costs were included, although it could be assumed that most of the omitted hospital costs were common to both treatments. One category that may not have been equivalent was the staff time necessary for administering the drug and this could have been documented in the article. The price year was not specified which could create problems in generalising the results to other settings. The mean differences in costs were analysed using student's t-tests, with the assumption that the mean difference is normally distributed. This may not be the case in a small sample (n=50) and non-parametric methods, such as the bootstrap method, would be more appropriate.
Other issues The authors did not make any comparisons of the results with findings from other studies. The issue of generalisability was addressed insofar as the authors advised that a switch to methadone treatment should be monitored with care due to the increase in side-effects that were uncommon during treatment with hydromorphone. The authors also advised caution in the interpretation of the results due to the study design.
Implications of the study Randomised controlled studies are required to clarify the equianalgesic ratio and to compare the analgesic and toxic effects of methadone to conventional opioids.
Bibliographic details Watanabe S, Belzile M, Kuehn N, Hanson J, Bruera E. Capsules and suppositories of methadone for patients on high-dose opioids for cancer pain: clinical and economic considerations. Cancer Treatment Reviews 1996; 22(Supplement A): 131-136 Indexing Status Subject indexing assigned by NLM MeSH Adult; Aged; Analgesics, Opioid /administration & Capsules; Female; Humans; Male; Methadone /administration & Middle Aged; Neoplasms /physiopathology; Pain, Intractable /drug therapy; Retrospective Studies; Suppositories; dosage; dosage AccessionNumber 21996000588 Date bibliographic record published 30/11/2000 Date abstract record published 30/11/2000 |
|
|
|