Slow Accrual

Primary Aims:

• To determine whether methadone used as first line strong opioid is superior to morphine as evidenced by reduced pain over a 12-week treatment period in patients with advanced cancer. Previous studies have demonstrated consistent improvement of pain control after opioid rotation from morphine to methadone. In addition, the pilot study showed that there was a trend towards lower pain intensity when methadone used as first line opioid as compared to morphine. Researchers postulate that due to its superior analgesic effects, methadone will result in better pain control over time as compared to morphine.
• To determine whether methadone used as first line strong opioid is superior to morphine as evidenced by reduced frequency of neurotoxicity, dose escalation and treatment failure over a 12-week treatment period. Previous studies have demonstrated that patients develop increased pain or neurotoxicity after chronic use of morphine and require frequent opioid escalation. Researchers postulate that methadone will demonstrate lower opioid induced neurotoxicity, less frequent dose escalation and less treatment failure over 12-week treatment period as compared to morphine.

Secondary Aim:

-To perform an economic evaluation, comparing the costs and clinical benefits of methadone and morphine. Researchers will perform an evaluation that incorporates both treatment and potential "downstream" costs, as well as an examination of clinical benefits that incorporate preferences, to perform an appropriate economic comparison. We postulate that methadone and its associated costs will be cheaper than morphine. However, if one strategy is both more expensive and clinically superior than the other, researchers are prepared to perform an incremental cost-effectiveness analysis. In that case, researchers expect to show that the greater pharmaceutical costs involved with morphine will make its use not be a cost-effective strategy.

STUDY DRUGS:

MORPHINE is recommended as the first choice of strong pain killers by the World Health Organization Pain Relief Guidelines.

METHADONE is recommended as the second choice of strong pain killers.

SCREENING TESTS:

Before you can start treatment on this study, you will have "screening tests." These tests will help the doctor decide if you are eligible to take part in this study. The following tests and procedures will be performed:

• You will be asked about your level of pain.
• You will be asked about any pain killers you are currently taking.
• You will be asked about your history of allergies.
• Blood (about 1 teaspoon) will be drawn to check your kidney function.

STUDY GROUPS:

If you are found to be eligible to take part in this study, you will be randomly assigned (as in the toss of the coin) to 1 of 2 treatment groups. Group 1 will receive morphine while on-study. Group 2 will receive methadone. You will have an equal chance of being placed in either group. Neither you nor any of the study staff will know which study drug you are receiving. However, if needed for your safety, the study staff and study doctor will be able to find out which study drug you are receiving.

STUDY DRUG ADMINISTRATION:

If you are in Group 1, you will take 1 morphine capsule every 12 hours with water. If you are in Group 2, you will take 1 methadone capsule every 12 hours. Morphine and methadone should be swallowed whole.

You will be given additional capsules in another bottle to take for excessive pain. The additional capsules should be taken every 2 hours, as needed. If you need 3 or more of these additional doses in 24 hours, you should contact the study staff.

STUDY VISITS:

You will return to the clinic at the end of Weeks 1, 2, 4, 6, 8, 10 and 12 for questionnaires about your pain levels, ability to sleep, constipation, other side effects, and quality-of-life. You will complete 6 questionnaires at the Weeks 1, 2, 6, 10, and 11 visit. You will complete 11 questionnaires at the Weeks 4, 8, and 12 visits. Each questionnaire will take 1-3 minutes to complete. The visit with the research nurse will last about 45 minutes to 1 hour. Your study drug supply will also be checked. You also will be asked about your overall health, non-health care questions, and activity level. At these visits, you will receive a new prescription for a 2-week supply of the study drug.

PATIENT DIARY:

You will be given a patient diary booklet before you start taking the study drug. You will be asked to record when you take the study drug, other medications you may be taking, and any side effects you experience. You will fill out the patient diary once a day. It will take less than 2 minutes to complete.

For the first week of the treatment, you will be contacted by the research nurse every day either in person (if you are in the hospital) or by phone to check for pain, side effects, and the number of pills you have taken.

You are allowed to take other medication, such as medications for constipation, nausea, and other drugs during the study. All changes in medication for either symptoms or complications must be recorded by the research nurse at each study visit.

LENGTH OF STUDY:

After the visit at the end of Week 12, you will be off-study. You will be taken off-study early if your pain gets worse or intolerable side effects occur.

This is an investigational study. Both morphine and methadone are FDA approved and commercially available. You will not be told which study drug you were receiving. Up to 250 patients will take part in this study. Up to 200 will be enrolled at M. D. Anderson.

Inclusion Criteria:

1. Patient has pain caused by advanced cancer (local recurrence or metastatic disease)
2. Patient reporting average pain score for the last 24 hours is >/= 4 on a numerical scale from 0 to 10 (0= no pain, 10=the worst possible pain).
3. Patient is receiving mild opioids (e.g. propoxyphene, codeine, tramadol, hydrocodone), mixed agonist/antagonist (e.g. buprenorphine) or no opioids.
4. Patient requires initiation of strong opioid for cancer pain.
5. Patient has the ability to receive morphine or methadone orally.
6. Patient has no known allergy or severe toxicity to morphine or morphine-like drugs (e.g. hydromorphone, oxycodone, oxymorphone, codeine, hydrocodone, levorphanol), or methadone or methadone-like drug (e.g. propoxyphene).
7. Patient has normal cognition defined as normal state of arousal and absence of obvious clinical findings of confusion, memory or concentration deficit.
8. Patient has normal renal function (creatinine and blood urea nitrogen (BUN) within normal limits) \

Adverse events collected from baseline to Day 85, anticipated study period 12 weeks.